3-Alkyl-2-(6-carboxyhexyl) cyclopentanones and esters and salts thereof

ABSTRACT

This disclosure describes compounds of the class of substituted 9-oxoprostanoic acids and the esters and cationic salts thereof, useful as antimicrobial agents, hypotensive agents, anti-ulcer agents, or as intermediates, and novel processes for preparing the same.

CROSS REFERENCE TO RELATED APPLICATION

This is a division of application Ser. No. 240,814, filed Apr. 3, 1972now U.S. Pat. No. 4,018,811 Which in turn is a continuation-in-part ofour copending application Ser. No. 225,680, filed Feb. 11, 1972 nowabandoned which in turn is a continuation-in-part of our copendingapplication Ser. No. 95,910, filed Dec. 7, 1970. now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention n to new organic compounds and, more particularly, isconcerned with substituted 9-oxoprostanoic acids3-alkyl-2-(ω-carboxyalkyl)cyclopentanones! and esters thereof which maybe represented by the following general formula: ##STR1## wherein R₁ ishydrogen or lower alkyl R₂ is a straight chain alkyl group having from 1to 10 carbon atoms, inclusive; and Z is a divalent radical selected fromthe group consisting of ##STR2## wherein m is an integer from 4 to 8,inclusive, q is an integer from 3 to 5, inclusive, R₃ is lower alkyl,and R₄ is lower alkyl, fluoro or phenyl. Suitable lower alkyl groupscontemplated by the present invention are those having up to four carbonatoms such as, for example, methyl, ethyl, isopropyl, sec-butyl, etc.The straight chain alkyl groups contemplated by the present inventionare methyl, ethyl, n-propyl, n-butyl, n-amyl, n-hexyl, n-heptyl,n-octyl, n-nonyl and n-decyl.

DETAILED DESCRIPTION OF THE INVENTION

Also embraced within the scope of the present invention are thenon-toxic, pharmaceutically acceptable salts of the substituted9-oxoprostanoic acids 3-alkyl-2-(ω-carboxyalkyl)cyclopentanones!. Thecations comprised in these salts include, for example, the non-toxicmetal cations such as the sodium ion, potassium ion, calcium ion, andmagnesium ion as well as the organic amine cations such as the tri(loweralkyl)amine cations (e.g., triethylamine), procaine, and the like.

The novel substituted 9-oxoprostanoic acids and esters thereof of thepresent invention are obtainable as yellow oils having characteristicabsorption spectra. They are relatively insoluble in water but arerelatively soluble in common organic solvents such as ethanol, ethylacetate, dimethylformamide, and the like. The cationic salts of thesubstituted 9-oxoprostanoic acids are, in general, white to yellowcrystalline solids having characteristic melting points and absorptionspectra. They are relatively soluble in water, methanol, and ethanol butare relatively insoluble in benzene, diethyl ether, and petroleum ether.

The prostaglandins are a family of closely related compounds which havebeen obtained from various animal tissues, and which stimulate smoothmuscle, lower arterial blood pressure, antagonize epinephrine-inducedmobilization of free fatty acids, and have another pharmacological andautopharmacological effects in mammals. See Bergstrom et al., J. Biol.Chem. 238, 3555 (1963) and Horton, Experientia 21, 113 (1965) andreferences cited therein. All of the so-called natural prostaglandinsare derivatives of prostanoic acid: ##STR3## The hydrogen atoms attachedto C-8 and C-12 are in trans configuration.

The novel compounds of the present invention may be readily preparedfrom 2-carbethoxycyclopentanone in accordance with the reaction schemesset forth in Flowsheets A through G. In particular, the requisite2-(ω-carbethoxyalkyl)cyclopent-2-en-1-one intermediates (VIII) may beprepared in accordance with the following reaction scheme:

    __________________________________________________________________________    FLOWSHEET A     ##STR4##     ##STR5##     ##STR6##     ##STR7##    __________________________________________________________________________

wherein m is as hereinabove defined and X is iodo or bromo. Inaccordance with this reaction scheme, the cyclopent-2-en-1-ones (VIII)are developed by first converting 2-carbethoxycyclopentanone (I) to thesodium enolate thereof by means of sodium hydride in dimethoxyethane andthen treating the sodium enolate with an ethyl ω-haloalkanoate (II).There is thus obtained the corresponding2-carbethoxy-2-(ω-carbethoxyalkyl)cyclopentanone (III) which is thenhydrolyzed and decarboxylated to afford the2-(ω-carboxyalkyl)cyclopentanone (IV). This acid is then esterified withethanol whereby the 2-(ω-carbethoxyalkyl)cyclopentanone (V) is obtained.The reaction conditions for carrying out the above sequence of reactionsare well known in the art. The conversion of the cyclopentanone (V) tothe enol acetate (VI) is effected by heating with acetic anhydride inthe presence of p-toluenesulfonic acid. Preparation of the enol acetate(VI) usually requires heating for a period of from about 8 to 36 hours.During this period, it is preferable to allow by-product acetic acid todistill out in order to force the reaction to completion. Thebromination of the enol acetates (VI) to the 2-bromocyclopentanones(VII) is preferably carried out in a two phase system as follows. Asolution of bromine in chloroform is added to a rapidly stirred mixtureof a solution of the enol acetate (VI) in chloroform and an aqueoussolution of an acid acceptor such as calcium carbonate or soda ash. Thisaddition is carried out at 0°-5° C. over a period of about half an hour,stirring is continued for an additional period of about half an hour toa few hours, and the product VII) is then isolated by standardprocedures. The dehydrobromination of the 2-bromocyclopentanones (VII)is preferably carried out in dimethylformamide with a mixture of lithiumbromide and lithium carbonate at the reflux temperature for a period ofabout 30 minutes to an hour or so. The so formed cyclopent-2-en-1-ones(VIII) are also isolated by standard procedures well known in the art.Substitution of X--(CH₂)_(q) --C(R₃)₂ ----CH₂ --CO₂ C₂ H₅ for (II) inFlowsheet A and carrying through the sequence of transformationsillustrated therein is productive of the following cyclopent-2-en-1-one(VIIIa): ##STR8## wherein X, q and R₃ are as hereinabove defined.

The required cyclopent-2-en-1-one intermediates of general structure(XVI), wherein in the side-chain has a lower alkyl group, fluorine atomor phenyl group alpha to the carbethoxy function, may be prepared inaccordance with the following reaction scheme: ##STR9## wherein q and R₄are as hereinabove defined, and Y is a methyl or p-tolylradical. Inaccordance with this reaction scheme, the2-(ω-carbethoxyalkyl)cyclopent-2-en-1-ones (IX), prepared as describedin Flowsheet A for the preparation of (VIII) where m is 2-4, inclusive,are converted to the corresponding1-methoximino-2-(ω-carbethoxyalkyl)-2-cyclopentenes (X) by treatmentwith methoxyamine. With the ring carbonyl function thus blocked it ispossible to effect a preferential reduction of the ester group bytreatment with diisobutylaluminum hydride. The resulting alcohol (XI) isconverted to a mesylate or tosylate derivative (XII), which undergoesdisplacement on treatment with the sodium salt of a diethyl substitutedmalonate (XIII) to provide the disubstituted malonate derivatives (XIV).Hydrolysis and decarboxylation as well as concomittant cleavage of themethoximino blocking group provides the desired2-(ω-carboxy-α-substituted alkyl)cyclopent-2-en-1-ones (XV), which arereadily converted to the corresponding ester (XVI) by the usual Fisherprocedure.

The requisite 2-(ω-carbethoxy-3-oxa-alkyl)cyclopent-2-en-1-ones (XXII)and 2-(ω-carbethoxy-3-thia-alkyl)cyclopent-2-en-1-ones (XXVI) may beprepared in accordance with the reaction schemes of Flowsheet C, whereinq is as hereinbefore defined. ##STR10##

In accordance with the reaction scheme shown in Flowsheet C, for thepreparation of the oxa derivatives (XXII), an appropriate2-(ω-carbethoxyalkyl)cyclopent-2-en-1-one (XVII) is converted to thecorresponding methoxime (XVIII), the ester function of which is thenpreferentially reduced with diisobutylaluminum hydride to afford themethoxime alcohol (XIX). The alcohol (XIX) is converted on treatmentwith n-butyl lithium to the lithio alcoholate, which then is O-alkylatedby reaction with ethyl bromoacetate to provide (XX). Hydrolysis withacetone-aqueous hydrochloric acid furnishes the deblocked keto-acid(XXI), which is the re-esterified with ethanol in the presence ofp-toluenesulfonic acid to give the required2-(ω-carbethoxy-3-oxa-alkyl)cyclopent-2-en-1-one (XXII). O-Alylation canalso be accomplished by treatment of the lithio alcoholate of (XIX) withsodium or other metal salt of bromoacetic acid, in which case the freecarboxylix acid corresponding to ester (XX) is obtained. Hydrolysis asfor (XX) provides the keto acid (XXI).

The preparation of the thia derivatives (XXVI), proceeds from theintermediate alcohol (XIX), which after conversion to the tosylateintermediate (XXIII) and reaction with the sodium salt of ethylmercaptoacetate furnishes intermediate (XXIV). Deblocking of XXIV withacetone-aqueous hydrochloric acid provides the keto-acid (XXV), which onre-esterification with ethanol gives the required2-(ω-carbethoxy-3-thia-alkyl)cyclopent-2-en-1-ones (XXVI).

Certain of the intermediate compounds of the present invention may beobtained by the conjugate 1,4-addition of an alanate salt to a2-substituted cyclopent-2-en-1-one. This novel procedure is set forth inthe following reaction scheme: ##STR11## wherein R' is a lower alkylgroup, preferably methyl or n-butyl, R is a straight chain alkyl grouphaving from 1 to 8 carbon atoms, and Z' is a divalent radical selectedfrom the group consisting of ##STR12## wherein m and q are ashereinabove defined and R₄ is a lower alkyl radical. The compounds(XXIX) are readily prepared by the conjugate 1,4-addition of an alanatesalt (XXVIII) to a 2-substituted cyclopent-2-en-1-one (XXVII). Theyields for this operation are usually high and a clean product,uncontaminated with 1,2-addition product, is usually obtained.Furthermore, the transfer of the alkene group is effected with retentionof the trans-configuration of the hydrogen atoms attached to the doublebond, and no reaction is noted at the carbethoxy function of (XXVII).Another noteworthy aspect of this reaction is that it does not require acatalyst. The alanate salts (XXVIII) are conveniently prepared by thereaction of an appropriate 1-alkyne (R--CaCH) with diisobutylaluminumhydride, followed by reaction with a lower alkyl lithium derivative,preferably methyl lithium or n-butyl lithium. Suitable 1-alkynes whichmay be thus employed are, for example, 1-propyne, 1-butyne, 1-pentyne,1-hexyne, 1-heptyne and 1-octyne. The reaction of the 1-alkyne withdiisobutylaluminum hydride cleanly provides the trans-double bond and ispreferably carried out in an inert solvent such as benzene, toluene, andthe like at temperatures in the range of 40°-60° C. for several hours.The solvent is removed in vacuo and the subsequent reaction with methylor n-butyl lithium is preferably carried out in an ether-type solventsuch as diethyl ether, dibutyl ether, tetrahydrofuran, and the like.This reaction is rapid and is preferably carried out at 0°-10° C. withcooling. The conjugate 1,4-addition of the resulting alanate salt(XXVIII) to the cyclopent-2-en-1-one (XXVII) is preferably carried outat ambient temperatures for a period of 12 to 24 hours. This reaction isalso best carried out in an ether-type solvent such as diethyl ether,dibutyl ether, tetrahydrofuran, and the like. The intermediatealanate-enolate adduct is then hydrolyzed in situ with dilutehydrochloric acid with cooling, and the products (XXIX) are isolated inthe usual manner well known in the art. The conversion of the esters(XXIX) to the acids (XXX) is readily accomplished by mild saponificationprocedures such as in 0.5N aqueous-methanolic KOH at room temperaturefor 20-48 hours.

The novel compounds of the present invention may be readily prepared bythe conjugate 1,4-addition of a Grignard reagent (XXXII) to a loweralkyl ester of a 2-(ω-carboxyalkyl)cycylopent-2-en-1-one (XXXI) inaccordance with the following reaction scheme: ##STR13## wherein R' is alower alkyl group having up to 4 carbon atoms, R₂ is as hereinabovedefined, and X is chloro, bromo or iodo. In general, Grignard reactionswith conjugated ketones provide 1,2-addition products; conjugate1,4-addition is usually accomplished when the reaction is carried out inthe presence of a cuprous chloride or cuprous acetate catalyst. It istherefore most unexpected that the reaction of a cyclopentenone (XXXI)with a Grignard reagent (XXXII) in the presence of either of theaforementioned catalysts does not give appreciable amounts of thedesired 1,4-conjugate addition product. The novel feature of our processis provided by the use, as a catalyst, of a cuprous halide complex witha trisubstituted phosphine, a trialkyl phosphonate, a tertiary amine ora heterocycle containing a basic nitrogen (e.g., pyridine). We havefound it preferable to use tributylphosphine-cuprous iodide complex; (C₄H₉)₃ P.CuI. Thus, the preferred procedure for the preparation of thelower alkyl esters of the substituted 9-oxoprostanoic acids (XXXIII)involves the reaction of a cyclopentenone (XXXI) with a Grignard reagent(XXXII) in the presence of a trialkylphosphine-cuprous iodide complex(e.g., tributylphosphine-cuprous iodide). This reaction is best carriedout in the usual way in an ether-type solvent such as diethyl ether,dibutyl ether, tetrahydrofuran, and the like, at room temperature for aperiod of time of from two to eighteen hours. The product (XXXIII) isthen obtained by hydrolyzing the intermediate magnesium halide-enolatederivative, preferably with ammonium chloride, and isolating in theusual manner. In order to carry out this process, X in the Grignardreagent (XXXII) may be chlorine, bromine or iodine; but is preferablyiodine.

Alternatively, conjugate 1,4-addition can also be effected by anotherprocess which involves treatment of a cyclopentenone (XXXI) with alithio dialkyl cuprate (XXXVII) in accordance with the followingreaction scheme: ##STR14## wherein R' and R'₂ are each a lower alkylgroup having from one to four carbon atoms and Z is as hereinabovedefined. The lithio dialkyl cuprate reagents (XXXVII) are prepared bytreatment of a lower alkyl lithium (XXXV) with cuprous iodide (XXXVI),preferably at low temperatures (-5° C. to -20° C.) in an ether-typesolvent. The reaction of (XXXI) with (XXXVII) is carried out in theusual way in an ether-type solvent at low temperatures (-5° C. to -20°C.) for a period of time of a few hours. The product (XXXIII) isobtained by quenching the reaction mixture with aqueous ammoniumchloride solution and isolating in the usual manner.

The esters (XXXIII) may be hydrolyzed to the acids (XXXIV) by treatmentwith mild alkali, for example, 0.1N KOH in 50% methanol-water at ambienttemperature for 15-20 hours. The acids (XXXIV) may be obtained directlyby employing a 2-(ω-carboxyalkyl)cyclopent-2-en-1-one as startingmaterial in lieu of the esters thereof (XXXI) but this is not preferredsince an additional mole equivalent of Grignard reagent (XXXII) must beemployed.

When the cyclopentanone esters (XXXIII) are formed by quenching of thereaction mixture with aqueous ammonium chloride solution, the relativestereochemical relationship of the two side-chains is not known withcertainty. However, in any case, the subsequent hydrolysis of (XXXIII)to (XXXIV) ensures the development, at least in predominant proportion,of the thermodynamically favored trans-relationship between the twoside-chains, as is depicted in structures (XXXIII) and XXXIV) of thereaction schemes of Flowsheets E and F. Alternatively, submission of theesters (XXXIII) to alkaline or acidic, but non-hydrolytic, conditions inan anhydrous alcoholic solvent will ensure formation of the favoredtrans-relationship.

Certain of the novel compounds of the present invention may be preparedby the catalytic hydrogenation of a substituted9-oxo-13-trans-prostenoic acid, or lower alkyl ester thereof, as setforth in the following reaction scheme: ##STR15## This reduction iscarried out with a noble metal catalyst in the usual manner for reducingdouble bonds. Reduction can also be accomplished with diimide as thereducing agent.

All of the compounds of this invention can be isolated and purified byconventional methods. Isolation can be accomplished, for example, bydilution of the reaction mixture with water, extraction with awater-immiscible solvent such as methoxylene chloride, ethyl acetate,benzene, cyclohexane, ether, toluene and the like, chromatography,adsorption on ion-exchange resins, distillation, or a combination ofthese. Purification of the compounds of this invention can beaccomplished by means known in the art for the purification ofprostaglandins and lipids, fatty acids, and fatty esters. For example,reverse phase partition chromatography, countercurrent distribution,adsorption chromatography on acid washed Florisil® (synthetic magnesiumsilicate) and acid washed silica gel, preparative paper chromatography,preparative thin layer chromatography, chromatography over silver loadedcation exchange resins, and combinations thereof can be used effectivelyto purify the compounds produced by the processes of this invention.

The racemic products and intermediates of this invention can be resolvedinto their optically active components by a number of methods ofresolution well known in the art. For example, acids can be treated withan optically active base such as cinchonine, quinine, brucine, d- or1-α-phenyletylamine and the like to produce distereoisomeric salts whichcan be separated by crystallization. Alternatively, the acid may beesterified with an optically active alcohol, e.g., d- or 1-methanol,estradiol 3-acetate, etc., and the diastereoisomeric esters thenresolved.

Resolution of the racemic prostaglandin-like compounds of this inventioncan also be accomplished by reverse phase and absorption chromatographyon an optically active support and adsorbent and by selectivetransformation of one isomer with a biologically-active prostaglandintransforming system. Such transformations can be carried out byincubation or perfusion using methods well established in the art,followed by isolation and recovery of the isomer resistant to themetabolic transformation applied.

The novel substituted 9-oxoprostanoic acids and esters and salts thereofof the present invention are useful as antimicrobial agents and possesantibacterial and antifugal activity in vitro against a variety ofstandard laboratory microorganisms as determined by the agar-dilutionstreak-plate technique. In this assay, the compounds to be tested aremade up to contain 2.5 mg. of test compound per milliliter of solution.Observing sterile techniques, two-fold serial dilutions are made of eachtest solution. One milliter of each of the original solutions and ofeach of the serial dilutions is then added to 9 ml. of warm sterilenutrient agar capable of supporting growth of the bacterial testcultures. A second set of agar dilutions is prepared identical to thefirst except that the nutrient agar is designed to support the growth ofthe fungal test cultures. The standard sterile nutrient agar solutionscontaining the different dilutions of the test compounds, along withsuitable and comparable control dilutions containing no test compound,are then allowed to cool in Petri dishes thereby forming solidified agarplates. The test bacteria, and yeast-like fungi are prepared for use bygrowing in broth overnight. The spores of the filamentous fungi areharvested from mature agar slant cultures and are suspended in sterilephysiological saline solution. A loopful of each of the resulting livesuspensions is then, still employing sterile techniques, streaked uponthe surfaces of each of the agar plates and the resulting streakedplates are then incubated. After an appropriate period of time, each ofthe streaks on each of the plates is inspected visually and the extent,if any, of bacterial or fungal growth is noted. The minimal inhibitoryconcentration (expressed in micrograms per millileter) is defined as theconcentration of test compound causing complete inhibition of growth ofany particular organism.

In a representative operation, and merely by way of illustration, theminimal inhibitory concentration of typical compounds of the presentinvention against a variety of test organisms as determined in theabove-described assay are set forth in Table I below:

                  TABLE I    ______________________________________                 Minimal inhibitory conc. (mcg/ml.)    Compound       (1)      (2)      (3)   (4)    ______________________________________    9-Oxoprostanoic acid                   25       100       50    50    Ethyl 9-Oxo-17,18,19,20-    tetranorprostanoate                   250      250      250   250    Ethyl 9-Oxo-15,16,17,18,    19,20-hexanorprostanoate                   62                250   250    Ethyl 9-Oxo-14,15,16,17,    18,19,20-heptanorpro-    stanoate       62       100       50    50    Ethyl 9-Oxo-3-Oxa-14,15,    16,17,18,19,20-heptanor-    prostanoate                      250   250    Ethyl 9-Oxo-10a-homo-14,    15,16,17,18,19,20-hepta-    norprostanoate 250                50    50    Ethyl 9-Oxo-18,19,20-    trinorprostanoate                   62                250    9-Oxo-7a,7b-bishomo-14,    15,16,17,18,19,20-hepta-    norprostanoic Acid               250   250    9-Oxo-14,15,16,17,18,    19,20-heptanorprostanoic    Acid                             250   250    ______________________________________     (1) Mycobacterium amegmatin, ATCC 606     (2) Microsporum gypseum, ATCC 14683     (3) Trichophyton tonsurans, NIH 662     (4) Trichophyton, mentagrophytes, E 11

Topical preparations containing the 9-oxoprostanoic esters, acids orcationic salts thereof, it is expected, will provide particularlyuseful. Such compositions would be designed for administration tosubjects exposed to, or infected with sensitive bacteria or fungi foreither treatment or prophylaxis and may include ointments, creams,emulsions, unguents, salves, emollients, sprays, washes or the like. Inaddition, the compounds may be used in the form of solutions,suspensions, emulsions, washes, powders, dusts, mists, soaps, sprays,aerosols, drenches, or other forms for the purpose of cleaning,disinfecting, or sterilizing surgical instruments, laboratory glasswareor instruments, hospital walls or other surface, linens, dishes,laboratory tables, coops, cages, or the like. Likewise these compoundsmight be incorporated into soaps, detergents, sprays or the like in thehome, farm, office or elsewhere with the purpose of preventing orminimizing infection or contamination with sensitive bacteria or fungi.Painting, spraying, immersion or other means of effecting contact may beapplied. The ester derivatives of this invention are also useful asintermediates for the preparation of the corresponding carboxylic acidsand salts thereof.

9-Oxoprostanoic acid is also a valuable central nervous systemdepressant of low toxicity and was shown to possess CNS depressantactivity as determined by animal experiments as follows. The compoundwas administered intraperitoneally in a 2 starch vehicle to groups ofsix mice at three or more graded dose levels. At 15-minute and 30-minuteintervals after treatment, each animal was placed on the midpoint of ahorizontal steel rod (1.55 cm. in diameter and about 6 dm. in length),positioned 45.7 cm. above the surface of the table, and forced to walktoward a platform at either end of the rod. The criterion of inabilityto perform this act was consistent slipping to the side or falling offthe rod. Effective dose for reduced rod-walking ability (RWD₅₀) werecalculated or approximated from the data, and the time of peak effectwas estimated from the data. One-half of the RWD₅₀ dose was givenintraperitoneally to each mouse in groups of five. At the time of peakeffect, as determined above, each group of mice was put into theacetophotometer for a period of five minutes and the motor activitycounts were recorded and compared to controls. Since the compoundappeared to reduce motor activity by 50%, it was administered toadditional groups of five mice at graded doses and tested similarly. Thedose (MDD₅₀) that caused a 50% reduction in motor activity wasestimated. In a representative operation, 9-oxoprostanoic acid was shownto reduce locomotor activity (MDD₅₀) at a dose of 19 mg./kg. of bodyweight (IP), This compound also shows anticonvulsant activity,protecting 40% of strychnine-treated mice at a dose of 50 mg./kg. ofbody weight (IP).

The novel compounds of the present invention are useful as hypotensiveagents and their prostaglandin-like hypotensive activity wasdemonstrated in the following test procedure. This procedure is amodification of the technique described by Pike et al., Prostaglandins,Nobel Symposium 2, Stockholm, June 1966; page 165, IntersciencePublishers (New York, 1967).

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250grams in weight were fastened to rat boards in a supine position bymeans of canvas vests and limb ties. The femoral area was infiltratedsubcutaneously with lidocaine and the iliac artery and vein were exposedand cannulated. Arterial blood pressure (systolic/diastolic) wasrecorded using a Statham P₂₃ Db pressure transducer-Offner dynographsystem. To obtain a stable blood pressure, the animals were anesthetizedbefore use with pentobarbital, 30 mg./kg. of body weight intravenously,and also were given hexamethonium bitartrate, 2 ,mg./kg. of body weightintravenously. The test compounds were prepared by ultrasonic dispersionin a saline-Tween 80® vehicle. A constant intravenous dose volume of 0.5ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg. ofbody weight. Increasing or decreasing doses were selected depending onthe dose response obtained In Table II below are set forth the minimaldoses required to produce a decrease of about 10 mm. in diastolic bloodpressure for typical compounds of the present invention.

                  TABLE II    ______________________________________                          Effective Dose                          (mg./kg. of    Compound              body weight)    ______________________________________    9-Oxoprostanoic Acid  2    Ethyl 9-Oxoprostanoate                          2    Ethyl 9-Oxo-17,18,19,20-tetranorpros-    tanoate               8    9-Oxo-7a,7b-bishomo-14,15,16,17,18,    19,20-heptanorprostanoic acid                          2-8    Ethyl 9-Oxo-10a-homo-14,15,16,17,18,    19,20-heptanorprostanoate                          8    Ethyl 9-Oxo-15,16,17,18,19,20-hexa-    norprostanoate        0.2-2    9-Oxo-14,15,16,17,18,19,20-heptanor-    prostanoic acid       2    Ethyl 9-Oxo-14,15,16,17,18,19,20-    heptanorprostanoate   8    ______________________________________

This hypotensive effect is short acting and a continuous infusion ofcompound is necessary to maintain the effect. Nevertheless, it isauthoritatively claimed that hypotension induced by prostaglandins is ofan ideal nature and therefore, despite the necessity of infusion, thesecompounds may be useful in the treatment of certain hypertensive crisissituations such as eclampsia. A description of this problem appears inthe Medical Letter of Drugs and Therapeutics (p. 31-32, issue of Apr. 3,1970). Also, in a news item from Medical World News, 10, 12 (August 1,1969), Dr. J. B. Lee, associate professor of medicine at St. LouisUniversity, is quoted as saying that the related prostaglandin Acompounds "might be useful in a hypertensive crisis such as eclampsia."The natural prostaglandins are only difficulty available, and at greatcost. Thus, although the prostaglandin congeners of this invention maybe less potent and larger doses would probably be necessary, the greateravailability of these congeners, when prepared by the methods of thisinvention, should provide a substantial economic advantage.

The novel compounds of the present invention are also effectiveinhibitors of gastric acid secretion and of ulcer development inexperimental animals, and thus are potentially valuable as agents forthe control of gastric acid secretion and of gastric erosion and asanti-ulcer agents. Gastric acid secretion inhibitory action is usuallymeasured by the "Shay rat" procedure.sup.(1,2) with some modificationsas follows.

The rats (male, CFE strain) were starved for 48 hours (water was givenad libitum) to permit evacuation of stomach contents. On the morning ofthe experiment, under ether anesthesia, the abdominal region was shavedand a midline incision (1-11/2inches) was made with a scapel. With thehelp of a closed curved hemostate the duodenum was picked up. Upongetting the duodenum into view, fingers were used to pull the stomachthrough the opening, the stomach was then gently manipulated withfingers to rid stomach of air and residual matter which were pushedthrough the pylorus. Two-5 inch sutures were drawn under thepyloric-duodenal puncture. A ligature, at the juncture, was formed withone of the threads. The second ligature was also formed but nottightened.

The test compound of the vehicle, usually 1 ml./100 g. body weight, wereinjected into the duodenum as close as possible to the first ligature.After injection the second ligature was tightened below the injectionsite to minimize leakage. The stomach was placed back through theopening into the abdominal cavity, the area of incision was washed withsaline and the incision was closed with autoclips. (Ocasionally, insteadof an intraduodenal injection, animals were dosed by the oral orsubcutaneous route. In the latter case, dosing was done thirty to sixtyminutes before the operation.)

Three hours later, the rats were decapitated and exanguinated, takingcare that blood did not drain into the esophagus. The abdominal cavitywas exposed by cutting with scissors and the esophagus close to thestomach was clamped off with a hemostat, the stomach was removed bycutting above the hemostat (the esophagus was cut) and between the twosutures. Extraneous tissue was removed, the stomach washed with salineand blotted on gauze. A slit was carefully made in the stomach which washeld over a funnel and the contents were collected in a centrifuge tube.The stomach was further cut along the outside edge and turned insideout. Two ml. H₂ O were used to wash the stomach contents into therespective centrifuge tube. The combined stomach contents and wash werethen centrifuged out for 10 min. in the International Size 2 Centrifuge(setting at 30). The supernatant was collected, volume measured andrecorded, 2 drops of a phenylphthalein indicator (1% in 95% ethanol)were added and the solution was titrated with 0.02N NaOH (or with 0.04NNaOH when large volumes of stomach contents were encountered) to pH 8.4(because of usual coloring of the stomach contents, phenolphthalein wasonly used to permit visual indication that the end point was near) andthe amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or morewere considered active. In a representative operation, and merely by wayof illustration, the results obtained with this assay with typicalcompounds of the present invention are given in Table III below.

                  TABLE III    ______________________________________                       Intraduodenal                       Dose; mg./kg.                                   Percent    Compound           of body weight                                   Inhibition    ______________________________________                       100             84    9-Oxo-14,15,16,17,18,19,20-hepta-                        50             53    norprostanoic acid  25             37                       100             93    Ethyl 9-Oxo-14,15,16,17,18,19,20-                        50             58    heptanorprostanoate                       100    (oral    78                              dose)    Ethyl 9-Oxo-15,16,17,18,19,20-                       100             81    hexanorprostanoate    Ethyl 9-Oxo-16,17,18,19,20-penta-    norprostanoate     100             54    Ethyl 9-Oxo-17,18,19,20-tetranor-    prostanoate        100             66    Ethyl 9-Oxo-18,19,20-trinor-    prostanoate        100             41    Ethyl 9-Oxo-6,7,14,15,16,17,18,    19,20-nonanorprostanoate                       100             88    Ethyl 9-Oxo-10a-homo-14,15,16,17,    18,19,20-heptanorprostanoate                       100             60    Ethyl 9-Oxo-7a,7b-bishomo-14,15,    16,17,18,19,20-heptanorprosta-                        50             73    noate    9-Oxo-7a,7b-bishomo-14,15,16,17,    18,19,20-heptanorprostanoic                       100             91    acid    9-Oxo-6,7,14,15,16,17,18,19,20-    nonanorprostanoic acid                        50             86    Ethyl 9-Oxo-3oxa-14,15,16,17,18, -19,20-heptanorprostanoate                       200             55    ______________________________________

The compounds of this invention also provide protection against theulcerogenic properties of indomethacin. This assay was carried out inthe following manner.

Rats were starved for 48 hours (water was given ad libitum).Indomethacin (20 mg./kg. of body weight) was administered by thesubutaneous route and one-half the dose of the test compound wasadministered by gavage at the same time. After three hours, the secondhalf of the test compound was administered, also by gavage. Five hoursafter the administration of indomethacin the animals were decapitatedand the stomachs removed. The stomachs were washed with distilled water,blotted on gauze, cut along the larger curvature, and the contentsrinsed with distilled water. The stomachs were spread out, pinned on acork and visualized under magnifying glass for ulcers. The criteria forscoring of ulcers was as previously reported. Abdel-Galil et al. Brit.J. Pharmac. Chemotherapy 33:1-14 (1968)!.

    ______________________________________    Score    ______________________________________    Normal stomach    Petechial hemorrhage or pin point ulcers    2    1 or 2 small ulcers    3    Many ulcers, a few large    4    Many ulcers, mainly large    ______________________________________

Control animals treated with indomethacin but not test compoundconsistently give scores of about 3.5-3.7. Control animals treated withneither indomethacin nor test compound give scores of about 0.5-0.8. Theresults obtained in this assay with typical compounds of the presentinvention are set forth in Table IV below. Compounds producing a scoreof 2.8 or lower are considered to be active.

                  TABLE IV    ______________________________________                        Total Oral                        Dose; mg./kg.    Compounds           of body weight                                     Score    ______________________________________    9-Oxo-14,15,16,17,18,19,20-hepta-    norprostanoic acid  25           1.8    Ethyl 9-Oxo-14,15,16,17,18,19,20-    heptanorprostanoate 100          1.2    9-Oxo-7a,7b-bishomo-14,15,16,17,18,    19,20-heptanorprostanoic acid                        25           2.0    ______________________________________

This invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation of2-carbalkoxy(methyl/ethyl)-2-(4-carbethosybutyl)cyclopentan-1-one

To a stirred solution of the sodium cyclopentanone carboxylate enolatein dimethoxyethane, prepared from 187 g. (1.248 moles) of2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g.(1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. ofdimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl5-iodovalerate. The reaction mixture is stirred and heated at reflux for18 hours. The mixture is cooled and filtered. The solvent is removedfrom the filtrate by evaporation and the residue is poured into dilutehydrochloric acid and extracted with ether. The combined extracts arewashed with water and saline, dried over magnesium sulfate andevaporated to give an oil. The oil is distilled under reduced pressureto give 274 g. of a light yellow oil, b.p. 140°-143° C. (0.17 mm).

EXAMPLE 2 Preparation of 2-(4-carboxybutyl)cyclopentan-1-one

A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethylesters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for20 hours. Solution occurs in approximately 1/2 hour. The solution iscooled and diluted with water and extracted with ether. The combinedextracts are washed with saline and dried over magnesium sulfate andevaporated. The residue is evaporated twice with toluene to give 144 g.of an oil.

EXAMPLE 3 Preparation of 2-(4-carbethoxybutyl)cyclopentan-1-one

A stirred solution of 124 g. (0.673 mole) of2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18hours. The solvent is evaporated and the residue is dissolved in ether.The ether solution is washed with saline, dilute sodium bicarbonatesolution and again with saline, dried over magnesium sulfate andevaporated. The oil is distilled under reduced pressure to give 149 g.of a colorless oil, b.p. 106°-109° C. (0.23 mm).

EXAMPLE 4 Preparation of2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 1, treatment of 2-cyclopentanonecarboxylate (mixed methyl and ethyl esters) with sodium hydride indimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil,b.p. 136°-137° C. (0.16 mm).

EXAMPLE 5 Preparation of 2-(3-carboxypropyl)cyclopentan-1-one

In the manner described in Example 2, treatment of 2-carbalkoxy(mixedmethyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one(Example 4) with a 20% hydrochloric acid and acetic acid mixture gives ayellow oil.

EXAMPLE 6 Preparation of 2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 3, treatment of2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonicacid monohydrate in ethanol gives a colorless oil, b.p. 93° C. (0.10mm).

EXAMPLE 7 Preparation of ethyl and methyl2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate

In the manner described in Example 1, ethyl and methyl 2-cyclopentanonecarboxylate is reacted with ethyl 7-bromoheptanoate to furnish thesubject product, b.p. 147° C. (0.09 mm).

EXAMPLE 8 Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one

In the manner described in Example 2, ethyl and methyl2-(6-carbethoxyhexyl)-1-cyclopentanone-2-carboxylate (Example 7) ishydrolyzed to furnish the subject product, b.p. 143° C. (0.05 mm).

EXAMPLE 9 Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one

In the manner described in Example 3,2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnishthe subject product, b.p. 110° C. (0.03 mm).

EXAMPLE 10 Preparation of ethyl (methyl)7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate

To a stirred suspension of 51 g. of sodium hydride (57% in mineral oil)in 675 ml. of dimethylformamide is added 200 g. of 2-cyclohexanonecarboxylate (60% ethyl - 40% methyl esters) over a 1-5 hr. period withexternal cooling to maintain the temperature at 20°-25° C. The reactionmixture is stirred at ambient temperature for 15 minutes and heated to50° C. over 15 minutes. To the stirred mixture is added 300 g. of ethyl7-bromoheptanoate during a 10 minute period. The reaction mixture isstirred at 50°-60° C. for 4 hours, cooled, and poured into water. Theproduct is obtained by ether extraction. The extract is washedsuccessively with water and saturated sodium chloride, dried andevaporated to give a liquid which is purified by distillation, IR 1735cm⁻¹ (ester carbonyls) and 1710 cm⁻¹ (ketone carbonyl).

EXAMPLE 11 Preparation of 7-(cyclohexan-1-on-2-yl)heptanoic acid

A stirred mixture of 380 g. of mixed methyl and ethyl esters of7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml. ofconcentrated sulfuric acid, 970 ml. of glacial acetic acid, and 970 ml.of water is refluxed for 22.5 hours. The cooled reaction mixture istreated with 380 g. of sodium carbonate and 2 liters of water and isextracted with ether. Acidic material is partitioned from the etherextract with 1.0M sodium carbonate. The aqueous phase is acidified withconcentrated hydrochloric acid and extracted with ether. The extract iswashed successively with water and saturated sodium chloride, dried, andevaporated to give an oil.

EXAMPLE 12 Preparation of ethyl 7-(cyclohexan-1-on-2-yl)heptanoate

A solution of 232 g. of 7-(cyclohexan-1-on-2)heptanoic acid in 2500 ml.of ethanol is refluxed for 4.5 hours with 3.8 g. of p-toluenesulfonicacid monohydrate. The solution is diluted with 200 ml. of benzene, andboiling is continued for 2 hours as 200 ml. of distillate is removed.The volume of the solution is concentrated to 500 ml. After dilutionwith 500 ml. of ether the solution is extracted with a solution preparedfrom 50 ml. of saturated sodium bicarbonate, 50 ml. of saturated sodiumchloride, and 100 ml. of water. The extract is washed with saturatedsodium chloride, dried, and evaporated. The product is purified bydistillation to give a liquid, IR 1740 cm⁻¹ (ester carbonyl) and 1715cm⁻¹ (ketone carbonyl).

EXAMPLE 13 Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene

A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one(Example 9) in 250 ml. of acetic anhydride containing 0.940 g. ofp-toluenesulfonic acid monohydrate is heated to boiling under partialreflux allowing distillate at 118° C. or less (i.e., acetic acid) toescape through a Vigreaux column equipped with a condenser to collectthe distillate. After 16 hours, during which period acetic anhydride isadded in portions in order to keep the solvent level at at least 100ml., the solution is cooled and poured cautiously into a stirred coldmixture of saturated sodium bicarbonate solution (400 ml.) and hexane(250 ml.). The resulting mixture is stirred for an additional 30 minutesduring which period solid sodium bicarbonate is added periodically toinsure a basic solution. The hexane layer is separated and washed withsaturated sodium chloride solution, dried with anhydrous magnesiumsulfate and taken to dryness. Distillation of the residual oil gives 102g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).

EXAMPLE 14 Preparation of1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene

In the manner described in Example 13, treatment of2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with aceticanhydride and p-toluenesulfonic acid monohydrate gives a yellow oil,b.p. 98°-103° C. (0.35 mm).

EXAMPLE 15 Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene

In the manner described in Example 13, treatment of2-(4-carbethoxybutyl)cyclopent-1-one (Example 3) with acetic anhydrideand p-toluenesulfonic acid monohydrate gives a yellow oil, b.p.109°-110° C. (0.37mm).

EXAMPLE 16 Preparation of ethyl7-(1-acetoxycyclohex-1-en-2-yl)heptanoate

A stirred solution of 28.0 g. of ethyl7-(cyclohexan-1-on-2-yl)heptanoate (Example 12), 170 mg. ofp-toluenesulfonic acid monohydrate, and 25.6 g. of acetic anhydride isheated for 5 hours while allowing 8.0 g. of distillate to distill. Thecooled solution is poured into a stirred, ice-cold mixture of 500 ml. ofsaturated sodium bicarbonate and 250 ml. of hexane. After one hour thehexane phase is separated, dried, and evaporated. The crude product isdistilled to give a liquid, IR 1760 cm⁻¹ (vinyl ester carbonyl) and 1740cm⁻¹ (ethyl ester carbonyl).

EXAMPLE 17 Preparation of 2-(6-carbethoxyhexyl)cyclopent-2-1-one

To a rapidly stirred mixture of 50 g. of1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 13) in 150 ml.of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooledin an ice bath, is added dropwise over a period of about 30 minutes, asolution of 30 g. of bromine in 50 ml. of carbon tetrachloride. Afterstirring for an additional 45 minutes the chloroform layer is separatedand washed successively with dilute sodium thiosulfate solution,saturated sodium chloride solution, dried with anhydrous magnesiumsulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,N-dimethylformamide andadded to a mixture of 33 g. of lithium bromide and 32 g. of lithiumcarbonate in 375 ml. of N,N-dimethylformamide, previously dried byrefluxing with 375 ml. of benzene under a Dean-Stark apparatus followedby distillation of the benzene. The mixture is stirred at the refluxtemperature for 30 minutes, then cooled and poured into 850 ml. ofice-cold water. The resulting mixture is acidified (cautiously) with 4Nhydrochloric acid and extracted with ether three times. The combinedether extracts are washed with saturated sodium chloride solution, driedwith anhydrous magnesium sulfate and taken to dryness under reducedpressure to afford 41.5 g. of the amber oil. In order to convert anyisomeric material to the desired product, 41.5 g. of the above materialis treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450ml. of absolute alcohol at the reflux temperature for 18 hours. Thesolution is taken to dryness under reduced pressure. The resulting gumis disssolved in ether and washed with saturated sodium bicarbonatesolution, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate and taken to dryness under reduced pressure. Theresidual oil is distilled to give 30.2 g. of product; b.p. 118° C. (0.05mm); λH_(max) MeOH 229 μ (ε9950): λ_(max) 5.75, 5,85, 6.15, 8.45 μ;vapor phase chromatography shows 99% product, containing 1%2-(6-carbethoxyhexyl)cyclopentan-1-one.

This product can be purified by the following procedure. A mixture of120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containingapproximately 5% of the saturated analogue, and 7.67 g. (10 molepercent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol isstirred at ambient temperatures for 18 hours and is then refluxed for 1hour. The mixture is cooled, the solvent is evaporated, and the residueis taken up into 150 ml. of chloroform and passed through a column of450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield acolorless oil containing <0.5% of the saturated impurity.

EXAMPLE 18 Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one

In the manner described in Example 17, bromination of1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 14) followed bydehydrobromination with lithium bromide and lithium carbonate isproductive of the subject compound.

EXAMPLE 19 Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one

In the manner described in Example 17, treatment of1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 15) with bromineand subsequent treatment of the brominated product with a mixture oflithium bromide and lithium carbonate in N,N-dimethylformamide isproductive of the subject compound. Treatment of this product withp-carboxyphenylhydrazine by the procedure of Example 17 furnishes aproduct which contains less than 0.5% of the corresponding saturatedketone.

EXAMPLE 20 Preparation of1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene

To a mixture of 35.97 g. (0.151 mole) of2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 17) and 15.0 g. (0.180mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol isadded 25 ml. of pyridine and the resulting solution is stirred for 20hours at ambient temperatures. The solvent is evaporated and the residueis partitioned between water and diethyl ether. The organic phase iswashed with water and saturated brine, dried (Na₂ SO₄), and the solventis evaporated to yield an oil. Distillation yields 38.7 g. of acolorless oil, b.p. 115°-118° C. (0.075 mm). IR (film): 1740, 1627,1053, 890 cm⁻¹. λ.sub. max (MeOH) 243 (13,000). NMRδ(CDCl₃): 3.89.

EXAMPLE 21 Preparation of1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene

To an ice cooled solution of 34.10 g. (0.128 mole) of1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 20) in 200ml. of benzene under nitrogen is added dropwise 225 ml. of a 25%solution of diisobutyl aluminum hydride in hexane. The resultingsolution is stirred for 2 hours at 0°-5° C., poured onto ice and dilutehydrochloric acid, and the aqueous phase is saturated with sodiumchloride. The organic phase is separated, washed with saturated brine,dried (Na₂ SO₄), and evaporated to yield an oil. The latter is dissolvedin 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p.62°-64° C. IR (KBr) 3260, 1630, 1059, 893 cm⁻¹. λ_(max) 243 (14,200).NMR (CDCl₃)δ: 2.37.

EXAMPLE 22 Preparation of1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene

To a solution of 5.00 g. (0.0222 mole) of1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 21) in 50 ml.of dry pyridine at 0° C. is added 8.45 g. (0.0444 mole) ofp-toluenesulfonyl chloride and the resulting solution is chilled at 5°C. overnight. The mixture is partitioned between 300 ml. of ice waterand diethyl ether. The organic phase is washed with 1:1 ice coldhydrochloric acid, cold water, and cold saturated brine, dried (NaSO₄/K₂ CO₃), and evaporated under reduced pressure at room temperature toyield an oil. The latter is dissolved in 600 ml. of hexane, treated with0.5 g. of Darco, filtered and evaporated to yield 7.7 g. of a colorlessoil. IR (film) 1600, 1192, 1182, 1053, 890 cm⁻¹. λ_(max) (MeOH) 228 and243.

EXAMPLE 23 Preparation of1-methoximino-2-(8,8-dicarbethoxyoctyl)-2-cyclopentene

To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g.(0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate ofExample 22 and the mixture is refluxed for 2 hours under a nitrogenatmosphere. The mixture is partitioned between cold dilute hydrochloricacid and diethyl ether, and the organic phase is washed with water andsaturated brine, dried (Na₂ SO₄), and evaporated to yield an oil. Theexcess diethyl malonate is distilled off under reduced pressure to yield6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm⁻¹.

EXAMPLE 24 Preparation of1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopentene

A mixture of 6.45 g. of the diester of Example 23 and 6.72 g. ofpotassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1hour, cooled, and is partitioned between water and diethyl ether. Theaqueous phase is acidified with hydrochloric acid, extracted with ether,and the organic phase is washed with water and saturated brine, dried(Na₂ SO₄) and evaporated to yield a solid. The solid is crystallizedfrom benzene to yield 4.15 g. of tan crystals, m.p. 135°-137° C.(--CO₂).

EXAMPLE 25 Preparation of1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene

A solution of 3.926 g. (0.0126 mole) of the diacid of Example 24 in 20ml. of xylene is refluxed for 1.5 hours, cooled, and evaporated to yielda tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm⁻¹.

EXAMPLE 26 Preparation of 2-(8-carboxyoctyl)cycopent-2-en-1-one

The acid methoxime from Example 25 is refluxed for 5 hours with 55 ml.of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled,the solvent is evaporated, and the residue is partitioned between waterand diethyl ether. The organic phase is washed with water and saturatedbrine, dried (Na₂ SO₄), and evaporated to yield a tan solid. IR (KBr)1745, 1665 cm⁻¹. λ_(max) (MeOH) 228 (12,600).

EXAMPLE 27 Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one

The acid ketone from Example 26 is Fisher esterified with 100 ml. ofabsolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonicacid for 6 hours, cooled, and the solvent is evaporated. The resultingoil is dissolved in 3:1 benzene-ether and the solution is passed througha column of 100 g. of Florisil® . The filtrate is evaporated and theresidue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139°C. (0.05 Torr).

EXAMPLE 28 Preparation of ethyl 7-(cyclohex-2-en-1-one-2-yl)heptanoate

To a stirred solution of ethyl 7-(1-acetoxycyclohex-1-en-2-yl)heptanoate(Example 16) in 750 ml. of acetic acid and 125 ml. of pyridine at 10° C.is added a solution of 13.8 g. of bromine in 200 ml. of acetic acid over20 minutes. The resulting solution is allowed to stand at ambienttemperature for 45 minutes and is then decolorized with sodium sulfite.The solution is poured into 800 ml. of half-saturated sodium chlorideand extracted with 1:1 hexane-ether. The extract is washed successivelywith water and saturated sodium chloride, dried over sodium carbonate,and evaporated to give 32 g. of the crude bromoketone. To a stirredsuspension of 14.2 g. of lithium bromide and 16.6 g. of lithiumcarbonate in 250 ml. of anhydrous dimethylformamide at 80° C. is addedthe above bromoketone. The stirred mixture is heated to boiling over 20minutes and refluxed for 15 minutes. The cooled mixture is poured into1000 ml. of water, acidified with dilute hydrochloric acid, andextracted with ether. The extract is washed successively with water andsaturated sodium chloride, dried, and evaporated. The product ispurified by distillation to give a liquid, IR 1740 cm⁻¹ (estercarbonyl), 1685 cm⁻¹ (ketone carbonyl), and 1650 cm⁻¹ (olefin); NMR(CCl₄) 6.63 (multiplet, vinyl proton).

EXAMPLE 29 Preparation of ethyl 9-oxo-13-trans-prostenoate

A solution of 1.102 g. of 1-octyne in 2 ml. of benzene is treated with11.5 ml. of 15% diisobutylaluminum hydride in toluene and the solutionis heated to 50° C. for 2 hours. The solution is cooled, its solvent isremoved in vacuo, and the resulting oil is treated with 5.45 ml. of5.10% methyl lithium in diethyl ether with ice cooling. To the resultingsolution is added 1.830 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone(Example 17) and the solution is stirred at ambient temperatures for 18hours. The solution is poured onto ice and dilute hydrochloric acid, andthe mixture is extracted with diethyl ether. The organic phase is washedwith dilute sodium bicarbonate, water, and saturated brine, dried, andevaporated. The residue is purified by chromatography on Florisil® anddistillation to yield 1.878 g. of an oil, IR 1736 cm⁻¹ (ester and ketonecarbonyls 969 cm⁻¹ (trans vinyl group); NMR (CDCl₃)δ 5.14-5.87(multiplet, 2H, vinyl protons, J trans═ 15 Hz); Mass Spectrum, parentpeak at 350 mu.

EXAMPLE 30 Preparation of ethyl9-oxo-18,19,20-trinor-13-trans-prostenoate

In the manner described in Example 29,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 17) is added to thereagent prepared from 1-pentyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by distillation to give a liquid, IR 1740 cm⁻¹(ester and ketone carbonyls) 967 cm⁻¹ (trans vinyl group).

EXAMPLE 31 Preparation of ethyl 9-oxo-20-nor-13-trans-prostenoate

A solution of 5.30 g. of 1-heptyne in 10 ml. of benzene is treated with40 ml. of 1.2N diisobutylaluminum hydride in hexane and heated at 50° C.for 2 hours. The solution is cooled in an ice bath and diluted with 25ml. of ether. To the solution is added 30 ml. of 1.6M n-butyl lithium inhexane. After stirring for 20 minutes at 15°-25° C. the resultingsolution is treated with a solution of2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 17). The mixture isstirred at 5°-25° C. for 18-20 hours and the product then is hydrolyzedwith a mixture of ice and hydrochloric acid. The crude product, obtainedfrom the organic phase, is purified by chromatography on silica gel togive an oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) and 967 cm⁻¹(trans vinyl group).

EXAMPLE 32 Preparation of ethyl 20 -methyl-9-oxo-13-trans-prostenoate

In the manner described in Example 31,2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 17) is added to thereagent prepared from 1-nonyne, diisobutylaluminum hydride and n-butyllithium. The crude product obtained by acid hydrolysis and evaporationof organic solvent is purified by chromatography on silica gel to givean oil, IR 1740 cm⁻¹ (ester and ketone carbonyls) and 967 cm⁻¹ (transvinyl group).

EXAMPLE 33 Preparation of ethyl 9-oxo-6,7-dinor-13-trans-prostenoate

In the manner described in Example 29,2-(4-carbethoxybutyl)-2-cyclopentenone (Example 19) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride, and methyllithium. The product is obtained by acid hydrolysis, ether extractionand distillation to yield a colorless oil, b.p. 149°-150° C. (0.075mm.). IR 1740 cm⁻¹ (ester and ketone carbonyls) 963 cm⁻¹ (trans-vinylgroup).

EXAMPLE 34 Preparation of ethyl9-oxo-7a,7b-bis-homo-13-trans-prostenoate

In the manner described in Example 29,2-(8-carbethoxyoctyl)-2-cyclopentenone (Example 27) is added to thereagent prepared from 1-octyne, diisobutylaluminum hydride, and methyllithium. The crude product obtained by acid hydrolysis and etherextraction is purified by silica gel chromatography to give an oil, IR1740 cm⁻¹ (ester and ketone carbonyls), 967 cm⁻¹ (trans-vinyl group).

EXAMPLE 35 Preparation of2-(4-carbethoxybutyl)-2-cyclopentenonemethoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 19) withmethoxyamine hydrochloride in the manner described in Example 20 givesan oil, b.p. 107°-109° C. (0.05 mm). IR (film): 1740, 1628, 1050, 885cm⁻¹. λ_(max) (MeOH) 243 (13,600).

EXAMPLE 36 Preparation of 2-(5-hydroxypentyl)-2-cyclopentenomethoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 35)with diisobutyl aluminum hydride in the manner described in Example 21gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm⁻¹.λ_(max) MeOH 243 (12,020).

EXAMPLE 37 Preparation of 2-(5-tosylpentyl)-2-cyclopentenomethoxime

Treatment of 2-(5-hydroxypentyl)-2-cyclopentenomethoxime (Example 36)with p-toluenesulfonyl chloride in pyridine in the manner described inExample 22 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885cm⁻¹.

EXAMPLE 38 Preparation of2-(6,6-dicarbethoxyoctyl)-2-cyclopentenomethoxime

To a solution of sodio diethyl ethymalonate, prepared from 1.63 g.(0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. ofethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethylmalonate, is added 7.5 g. of tosylate from Example 37 in 20 ml. ofethylene glycol dimethyl ether and the mixture is refluxed for 3 hoursand then allowed to stand at room temperature for 18 hours undernitrogen atmosphere. The reaction mixture is filtered and most of thesolvent is removed. The mixture is partitioned between cold dilutehydrochloric acid and diethyl ether, and the organic phase is washedwith water and saturated brine, dried (MgSO₄), and evaporated to yieldan oil. The excess ethyl diethyl malonate is distilled off under reducedpressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627,1050, 885 cm⁻¹.

EXAMPLE 39 Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenomethoxime

Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenomethoxime (Example38) with potassium hydroxide, and 1:1 aqueous methanol in the mannerdescribed in Example 24 gives a light yellow oil.

EXAMPLE 40 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenomethoxime

In the manner described in Example 25, treatment of2-(6,6-dicarboxyoctyl)-2-cyclopentenomethoxime (Example 39) with xyleneat reflux for 18 hours gives a yellow oil.

EXAMPLE 41 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenomethoxime (Example 40)with acetone and 2N hydrochloric acid in the manner described in Example26 gives a light yellow oil.

EXAMPLE 42 Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 41) withthionyl chloride and then treatment of the acid chloride with ethanol inthe usual manner gives an amber oil. The oil is placed on amagnesia-silica gel column and eluted with 3:1 benzene:ether. Thesolvent is removed and the residue is distilled, b.p. 122° C. (0.06 mm).

EXAMPLE 43 Preparation of diethyl1,1-dimethyl-5-tetrahydropyranylpentylmalonate

To 486 mg. (0.02 g.-atoms) of magnesium in 5 ml. of toluene containingone molar equivalent of tetrahydrofuran per equivalent of magnesium andone percent iodine (calculated in weight of magnesium) is added dropwise3.86 g. (0.02 mole) of 4-chloro-1-tetrahydropyranyloxybutane over aperiod of one hour with stirring, under nitrogen at 70° C. The reactionmixture is stirred at 70° C. for four hours. This reagent is then addeddropwise to 3 g. (0.015 mole) of ethyl isopropylidenemalonate in 40 ml.of tetrahydrofuran containing 392 mg. of tetrakisiodo(tri-n-butylphosphine)copper (I)! and stirred at room temperaturefor 2 hours. The reaction mixture is poured into cold dilutehydrochloric acid and extracted with ether. The ether extract is driedover magnesium sulfate and concentrated to give 5.92 g. of subjectproduct as an oil.

EXAMPLE 44 Preparation of diethyl 1,1-dimethyl-5-hydroxypentylmalonate

A solution of 3.5 g. (0.01 mole) of diethyl1,1-dimethyl-5-tetrahydrofuranyloxypentylmalonate in 70 ml. of ethanolcontaining 3 ml. of hydrochloric acid is allowed to stir at roomtemperature for 18 hours. The solution is concentrated, diluted withwater and extracted with ether. The ether extract is washed with water,dried over magnesium sulfate and concentrated to give 3.262 g. of alight yellow oil. The oil is purified by distillation, b.p. 116°-117° C.(0.05 mm).

EXAMPLE 45 Preparation of 3,3-dimethyl-7-hydroxyheptanoic acid

A mixture of 32 g. (0.117 mole) of diethyl1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and600 ml. of methanol-water (1:1) is heated at reflux for 8 hours and thenallowed to stand at room temperature for 18 hours. The methanol isremoved, diluted with water and the reaction mixture is acidified withconcentrated hydrochloric acid. The mixture is extracted with ether. Theextract is washed with water and saline, dried over anhydrous magnesiumsulfate and concentrated to give 27 g. of1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hoursand then allowed to stand at room temperature overnight. The solution isremoved and the reaction mixture is diluted with water and extractedwith ether. The organic solution is washed with saline, dried overmagnesium sulfate and concentrated to give 18 g. of product as an oil.

EXAMPLE 46 Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3.484 g. (0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoicacid in 25 ml. of chloroform containing 3 drops of dimethylformamide isadded 5.8 ml. (0.08 mole) of thionyl chloride and the solution is thenheated at reflux for 3-4 hours. The solution is concentrated to give theintermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acidchloride is dissolved in a minimum amount of benzene and added slowly to20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. Thesolution is heated at reflux for one hour and then concentrated. Theresidue is dissolved in ether, washed with water, dilute sodiumbicarbonate solution and saline. The organic solution is dried overmagnesium sulfate and concentrated to give 3.57 g. of product as ayellow oil.

EXAMPLE 47 Preparation of ethyl 3,3-dimethyl-7-iodoheptanoate

To a solution of 3.57 g. (0.0162 mole) of ethyl3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone isadded 4 g. of sodium iodide and the mixture heated at reflux for 18hours. The reaction mixture is cooled, filtered and concentrated. Theresidue is partitioned between ether and water. The aqueous phase isextracted several times with ether. The extract is washed with sodiumbisulfite solution, water and saline. The organic solution is dried overmagnesium sulfate and concentrated to give 4.182 g. of a yellow oil. Thematerial is purified by distillation, b.p. 86°-87° C. (0.18 Torr).

EXAMPLE 48 Preparation of2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one

This compound is prepared by treatment of sodio cyclopentanonecarboxylate enolate with ethyl 3,3-dimethyl-7-iodoheptanoate by theprocedure described in Example 1.

EXAMPLE 49 Preparation of2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one

This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixedmethyl and ethylester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by theprocedure described in Example 2.

EXAMPLE 50 Preparation of2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one

Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one withethanol is productive of the subject compound.

EXAMPLE 51 Preparation of1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene

This compound is prepared from2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydrideby the process described in Example 13.

EXAMPLE 52 Preparation of2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

This compound is prepared from1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene viabromination and dehydrobromination according to the procedure describedin Example 17.

EXAMPLE 53 Preparation of2-(3-carbethoxypropyl)-1-methoxyimino-2-cyclopentene

In the manner described for the preparation of the compound of Example20, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from2-(3-carbethoxypropyl)-2-cyclopentenone (Example 18) and methoxyaminehydrochloride.

EXAMPLE 54 Preparation of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example21, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene anddiisobutylaluminum hydride.

EXAMPLE 55 Preparation of2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene

To an ice cold solution of 4.833 g. (0.0266 mole) of2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of drytetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyllithium in hexane, dropwise. The reaction mixture is stirred for 0.5hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is addeddropwise. The reaction mixture is stirred overnight at room temperatureand then refluxed for 1.5 hours. The reaction is cooled and poured intowater and extracted several times with ether. The ether extracts arewashed with saline, dried over magnesium sulfate, and concentrated. Theresidue is placed on an alumina column, chloroform being used as a washsolvent. The combined washings are concentrated to dryness to give 4.903g. of product as a yellow oil.

EXAMPLE 56 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 26, treatment of2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetoneand 2N hydrochloric acid at reflux gives the subject compound as ayellow oil.

EXAMPLE 57 Preparation of 2-(6-carbethoxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 27, treatment of2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid inethanol produces the subject product as a light yellow oil.

EXAMPLE 58 Preparation of2-(4-p-toluenesulfonyloxybutyl)-1-methoxomino-2-cyclopentene

In the manner described in Example 22, treatment of2-(4-hydroxybutyl)-1-methoxyimino-2-cyclopentene with p-toluene sulfonylchloride in pyridine gives the subject product as a light yellow oil; IR(film): 1600, 1190, 1050, 885 cm⁻¹.

EXAMPLE 59 Preparation of2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene

To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2%in mineral oil) in 50 ml. of dimethoxyethane, under nitrogen, is addedslowly 4.8 g. (0.0347 mole) of ethyl-2-mercaptoacetate. The reactionmixture is stirred at room temperature for one hour and then a solutionof 7.8 g. (0.0231 mole) of2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml.of dimethoxyethane is added dropwise and stirred at room temperature for18 hours. The solution is heated at reflux for one hour, cooled andpoured into cold dilute hydrochloric acid and then extracted with ether.The combined ether extracts are washed with saline, dried over magnesiumsulfate and evaporated to give 7.6 g. of subject product as a yellowoil.

EXAMPLE 60 Preparation of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 26, treatment of2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetoneand 2N hydrochloric acid at reflux gives the subject product as a yellowoil.

EXAMPLE 61 Preparation of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 27 treatment of2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acidin ethanol gives the subject ester as a yellow oil.

EXAMPLE 62 Preparation of2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene

To an ice cold solution of 3.66 g. (0.02 mole) of2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene (Example 54) in 50 ml.of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 Mn-butyl lithium in hexane. The reaction mixture is stirred for half anhour and then the lithium salt of chloroacetic acid, prepared from 1.89g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6M n-butyl lithiumin 20 ml. of dimethoxyethane, is added and the reaction mixture isheated at reflux for 48 hours. The solvent is evaporated and the residueis partitioned between ether and water. The aqueous phase is acidifiedwith hydrochloric acid and extracted with ether. The organic phase iswashed with water and saturated saline solution, dried (MgSO₄), andevaporated to give 3.35 g. of a yellow oil.

EXAMPLE 63 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopenten-1-one

In the manner described in Example 26, treatment of2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 62) withacetone and 2N hydrochloric acid at reflux gives the subject compound asa yellow oil.

EXAMPLE 64 Preparation of1-methoximino-2-(4-methanesulfonyloxybutyl)-2-cyclopentene

To a solution of 1.83 g (0.01 mole) of1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 54) in 10 ml.of methylene chloride containing 1.52 g. (0.015 mole) of triethylamineis added 1.265 g. (0.011 mole) of methanesulfonyl chloride over a periodof 5-10 minutes at 10°-0° C. Stirring is continued for 15 minutes andthe solution is then washed with cold water, cold 10% hydrochloric acid,cold sodium bicarbonate solution, and cold saline solution. The organicphase is dried (MgSO₄) and concentrated to give an oil which solidifiesupon cooling. Crystallization from ether-petroleum ether (30°-60° C.)gives 1.797 g. of white crystals, m.p. 67°-68° C.

EXAMPLE 65 Preparation of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene

A mixture of 2.75 g. (0.01 mole) of1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 75)and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dryN,N-dimethylformamide is heated at 65°-70° C. for 3 hours. The cooledreaction mixture is poured into water and extracted with diethyl ether.The organic phase is washed with water and saturated saline solution,dried (MgSO₄), and evaporated to give 1.89 g. of a light yellow oil.

EXAMPLE 66 Preparation of1-methoximino-2-(5-carboxypentyl)-2-cyclopentene

A mixture of 1.89 g (0.0092 mole) of1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 65) and 1 g.(0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol isrefluxed for 48 hours, cooled, and partitioned between water and diethylether. The aqueous phase is acidified with hydrochloric acid, extractedwith diethyl ether, and the organic phase is washed with water andsaturated saline solution, dried (MgSO₄), and evaporated to give 1.86 g.of a yellow oil.

EXAMPLE 67 Preparation of 2-(5-carboxypentyl)-2-cyclopentenone

A solution of 1.86 g. (0.00825 mole)1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 66) in 44 ml.of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours.The solvent is partially evaporated and a solid precipitates and iscollected. The residue is extracted with diethyl ether and the organicphase is washed with saturated saline solution, dried (MgSO₄), andevaporated to yield additional solid. The combined solid material iscrystallized from ether/pet ether (30°-60° C) to yield crystallinematerial, m.p. 70°-72° C.

EXAMPLE 68 Preparation of 2-(5-carbethoxypentyl)-2-cyclopentenone

A solution of 1.309 g. (0.00668 mole) of2-(5-carboxypentyl)-2-cyclopentenone (Example 67) and 90 mg. ofp-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours.The solvent is evaporated and the residue is dissolved in ether. Theorganic phase is washed with water, sodium bicarbonate solution, andsaturated saline solution, dried (MgSO₄), and evaporated to give 1.371g. of a light yellow oil.

EXAMPLE 69 Preparation of2-(5-acetoxypentyl)-2-carbomethoxy/carbethoxy-cyclopentanone

A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200g. (8.3 moles) of mineral oil free sodium hydride in 10.1 of1,2-dimethoxyethane, 1320 g. (8.0 moles) of 5-chloro-1-amyl acetate M.E. Synerholm, Journ. Amer. Chem. Soc., 69, 2681 (1947)!; and 1200 g.(8.0 moles of sodium iodide is refluxed under nitrogen for 18 hours. Themixture is cooled, concentrated to 4.1 and partitioned between dilutehydrochloric acid and diethyl ether. The organic phase is washed withwater and saturated brine, dried (MgSO₄), and evaporated to yield 1920g. of an oil.

EXAMPLE 70 Preparation of2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxypentyl)-cyclopentanone

A mixture of 4,500 g. (16.2 moles) of2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example69), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloricacid, and 1 l. of water is refluxed for 18 hours, cooled and partitionedbetween saturated brine and benzene. The organic phase is washed withsaturated brine, dried (MgSO₄), and evaporated in vacuo to yield 3155 g.of an oil.

EXAMPLE 71 Preparation of 1-acetoxy-2-(5-acetoxypentyl)-1-cyclopentene

A solution of 400 g. (2.04 moles) of a mixture of2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone(Example 70) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. ofacetic anhydride is refluxed at a rate to maintain a steady distillationof acetic acid from the reaction through a helix-packed fractionationcolumn. The reaction is continued with the addition of acetic anhydrideto maintain a constant volume until complete conversion of startingmaterials to product is evident. The mixture is cooled and partitionedbetween 2 l. of hexane and 3 l. of cold water containing solid sodiumbicarbonate to maintain a neutral pH. The organic phase is washed withsaturated brine, dried (MgSO₄), and evaporated to yield 452 g. of anoil.

EXAMPLE 72

Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone

To a well stirred mixture of 405 g. (4.05 moles of calcium carbonate, 3l. of water, and 2.5 l. of chloroform cooled to 5° C. is addedsimultaneously 1016 g. (4.0 moles) of1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 71) and asolution of 648 g. (4.05 moles) of bromine in 500 ml. of carbontetrachloride at a rate to maintain a temperature below 10° C. Themixture is stirred for half an hour after addition of the ragents andthe phases are then separated. The organic phase is washed with 2%sodium thiousulfate solution, water, and saturated brine, dried (MgSO₄),and evaporated in vacuo to an oil. The oil is immediately added to arefluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l ofN,N-dimethylacetamide under nitrogen and the mixture is then refluxedfor thirty minutes. The mixture is cooled, filtered, and partitionedbetween water amd diethyl ether. The organic phase is washed with waterand sarturated brine, dried (MgSO₄), and evaporated to yield 757 g. ofan oil, b.p. 116°-118° C. (0.25 mm.).

EXAMPLE 73 Preparation of1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene

In the manner described for Example 20, 2-(5-acetoxypentyl)-2-cyclopentenone (Example 72) is treated with methoxyamine hydrochloridein pyridine and ethanol to yield the subject compound, b.p. 101°-103° C.(0.20 mm.).

EXAMPLE 74 Preparation of1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene

A mixture of 74 mg. (0.22 mole) of1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 73) and 56 g.(1.0 mole of potassium hydroxide in 300 ml. of 1:1 aqueous methanol isrefluxed for 2 hours and then cooled. The solvent is partially removedin vacuo and the residue is partitioned between saturated brine anddiethyl ether. The organic phase is washed with saturated brine, dried(MgSO₄), and evaporated to yield an oil which crystallized, m.p. 35°-36°C.

EXAMPLE 75 Preparation of1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene

To a cold solution of 9.85 g. (0.05 mole) of1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 74) and 7.6 g.(0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10°C. is added 6.3 g. (0.055 mole) of methanesulfonyl chloride at a rate tomaintain a temperature of -10° to 0° C. The mixture is then stirred for15 minutes and the poured into ice water. The organic phase is washedwith cold 10% hydrochloric acid, cold saturated sodium bicarbonatesolution, and cold saturated brine, dried (MgSO₄), and evaporated toyield a solid, m.p. 78°-80° C.

EXAMPLE 76 Preparation of 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene

To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, preparedfrom 248 g. (1.55 moles) of diethyl malonate and 1.72 g. (0.95 mole) ofmineral oil free sodium hydride in 1 l. of 1,2-dimethoxyethane undernitrogen, is added 170 g. (0.62 mole) of1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 75)in 1.5 l. of 1,2-dimethoxyethane and the mixture is refluxed for 5hours. The mixture is cooled, filtered, and the solvent is evaporated.The residue is partitioned between cold dilute hydrochloric acid andwater, and the organic phase is washed with saturated brine, dried(MgSO₄), and evaporated to remove solvent and excess diethyl malonate toyield 209 g. of an oil.

EXAMPLE 77 Preparation of1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene

In the manner described in Example 24,1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated withpotassium hydroxide in 1:1 aqeuous methanol and then hydrochloric acidto yield the desired compound as crystals from diethyl ether, m.p.110°-115° C.

EXAMPLE 78 Preparation of1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene

A solution of 141 g. (0.50 mole) of1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. ofbis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, andevaporated to yield an oil. The latter is crystallized from hexane toyield 92 g. of solid, m.p. 70°-72° C.

EXAMPLE 79 Preparation of 2-(6-carboxyhexyl)-2-cyclopentenone

In the manner described in Example 26, treatment of1-methoximino-2-(6-carboxyhexyl)-2-cyclopenten (Example 78) with acetoneand 2N hydrochloric acid at reflux provides the subject compound.

EXAMPLE 80 Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone

Fischer estification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example 79)in the manner of Example 27 provides the subject compound.

EXAMPLE 81 Preparation of1-methoximino-2-(6-fluoro-6,6-dicarbethoxyhexyl)-2-cyclopentene

To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g.(0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dryN,N-dimethylformamide and 8.174 g. (0.0458 mole) of diethylfluoromalonate is added dropwise 11.32 g. (0.0413 mole) of1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 75)in 60 ml. of N,N-dimethylformamide. The mixture is refluxed for 2 hoursunder a nitrogen atmosphere. The mixture is concentrated and partitionedbetween cold dilute hydrochloric acid and diethyl ether, and the organicphase is washed with saturated brine, dried (MgSO₄), and evaporated toyield 13.631 g. (92%) of a yellow oil.

EXAMPLE 82 Preparation of1-methoximino-2-(6-fluoro-6,6-dicarboxyhexyl)-2-cyclopentene

A mixture of 13.631 g. of the diester of Example 81 and 16 g. ofpotassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5hours, cooled, concentrated, and is partitioned between water anddiethyl ether. The aqueous phase is acidified with hydrochloric acid,extracted with ether, and the organic phase is washed with saturatedbrine, dried (MgSO₄) and evaporated to yield a solid. The solid iscrystallized from diethyl ether petroleum ether (30°-60° C.) to give 10g. (90%) of white crystals, m.p. 143°-145° C. (--CO₂).

EXAMPLE 83 Preparation of1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene

A solution of 10 g. of the diacid of Example 82 in 60 ml. of2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated toyield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethylether-petroleum ether (30°-60° C.) to give white crystals, m.p. 98°-100°C.

EXAMPLE 84 Preparation of2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one

The acid methoxime (8.5 g.) from Example 83 is refluxed for 5 hours with180 ml. of acetone and 84 ml. of 2N hydrochloric acid. The mixture iscooled, the solvent is evaporated, and the residue is partitionedbetween water and diethyl ether. The organic phase is washed withsaturated brine, dried (MgSO₄) and evaporated to yield 7.4 g. (98%) of alight yellow oil.

EXAMPLE 85 Preparation of2-(6-fluoro-6-carbethoxyhexyl)cyclopent-2-en-1-one

The acid ketone (7.4 g.) from Example 84 is Fisher esterified with 300ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18hours, cooled, and the solvent is evaporated. The resulting oil isdissolved in ether, washed with dilute sodium bicarbonate solution, andsaline, dried (MgSO₄), and evaporated to give 7.306 g. (86%) of a lightyellow oil.

EXAMPLE 86 Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene(Example 22) with sodium cyanide in the manner of Example 65 isproductive of the subject compound.

EXAMPLE 87 Preparation of2-(7-carboxyheptyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene(Example 86) by procedure of Example 66 is productive the subjectcompound.

EXAMPLE 88 Preparation of 2-(7-carboxyheptyl)-2-cyclopenten-1-one

Hydrolysis of the methoxime of Example 87 with acetone-hydrochloric acidby the procedure of Example 67 is productive of the subject compound.

EXAMPLE 89 Preparation of 2-(7-carbethoxyheptyl)-2-cyclopenten-1-one

Fisher esterification of the carboxylic acid of Example 88 by theprocedure of Example 68 is productive of the subject compound.

EXAMPLE 90 Preparation of2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene(Example 75 ) with sodio diethyl phenylmalonate by the procedure ofExample 76 is productive of the subject compound.

EXAMPLE 91 Preparation of2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example90) by the procedure of Example 24 is productive of the subject diacid.

EXAMPLE 92 Preparation of2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Decarboxylation of2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example91) by the procedure of Example 78 is productive of the subjectcompound.

EXAMPLE 93 Preparation of2-(6-carboxy-6-phenylhexyl)-2-cyclopentene-1-one

Methoxime cleavage of2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 92) inthe manner of Example 84 is productive of the subject ketone.

EXAMPLE 94 Preparation of2-(6-carbethoxy-6-phenylhexyl)-2-cyclopenten-1-one

Fisher esterification of the carboxylic acid of Example 93 in the mannerof Example 85 is productive of the subject keto-ester.

EXAMPLE 95 Preparation of2-(6-fluoro-6,6-dicarbethocyhexyl)-1-methoximino-2-cyclopentene

An ethanolic solution of sodium ethoxide, prepared from 0.389 g. ofsodium and 40 ml. of absolute ethanol, is treated at ambienttemperatures with 5.05 g. of2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 76). Theresulting solution is cooled to -20° C. and then treated with a streamof perchloryl fluoride until the mixture becomes neutral. The excessperchloryl fluoride is removed with a stream of nitrogen and the mixtureis retreated with 10 ml. of an ethanolic solution of sodium ethoxide(from 0.350 g. of sodium) and then with perchloryl fluoride until themixture becomes neutral. The excess perchloryl fluoride is removed witha stream of nitrogen and the mixture is filtered and evaporated to anoil. The latter is partitioned between ether and water and the organicphase is washed with saturated saline, dried (Na₂ SO₄) and evaporated toafford the subject compound.

EXAMPLE 96 Preparation of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene

A mixture of 15.24 g. of2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene (Example58) and 10.70 g. of sodium bromide in 100 ml. of dimethylsulfoxide isstirred at ambient temperature for 48 hours and then poured into 600 ml.of water. The mixture is extracted with hexane and its organic phase iswasted with saturated brine, dried (NaSO₄), and evaporated to yield atan oil.

EXAMPLE 97 Preparation of 2-(4-iodobutyl)-1-methoximino-2-cylopentene

To a solution of 1.5 g. of sodium iodide in 20 ml. of acetone is added2.3 g. of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene (Example 96) andthe resulting mixture is stirred at ambient temperatures for 5 hours.The mixture is filtered and evaporated and the residue is partitionedbetween water and benzene. The organic phase is washed with saturatedbrine, dried (NaSO₄), and evaporated to yield a tan oil.

EXAMPLE 98 Preparation of1-methoximino-2-(5-chloropentyl)-2-cyclopentene

A solution of 5 g. (0.0182 mole) of2-(5-methylsulfonyloxypentyl)-2-cyclopentenone methoxime (Example 75)and 5 g. of lithium chloride in 100 ml. of N,N-dimethylformamide isheated at reflux for 1 hour. The solution is cooled and 100 ml. of wateris added and extracted with diethyl ether. The combined extracts arewashed with saline, dried (MgSO₄), and evaporated to yield a lightyellow oil.

EXAMPLE 99 Preparation of1-methoximino-2-(6,6-dicarbethoxyhexyl)cyclopent-2-ene

Treatment of 1-methoximino-2-(5-chlorophenyl)-2-cyclopentene (Example98) with sodio diethylmalonate in the manner of Example 76 is productiveof the subject compound.

EXAMPLE 100 Preparation of1-methoximino-2-(5,5-dicarbethoxypentyl)-2-cyclopentene

Treatment of 2-(4-iodobutyl)-1-methoximino-2-cyclopentene (Example 97)or of 2-(4-bromobutyl)-1-methoximino-2-cyclopentene (Example 96) withsodio diethylmalonate in the manner of Example 76 is productive of thesubject compound.

EXAMPLE 101 Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one Bagli etal., Tetrahedron Letters, No. 5, 465 (1966)! in 1400 ml. of n-butanolcontaining 2.7 g. of p-toluenesulfonic acid monohydrate is allowed tostand at room temperature in a stoppered flask for about 24 hours. Thesolution is taken to dryness. The residue is taken up in ether and theethereal solution is washed several times with saline solution, driedwith anhydrous magnesium sulfate, and taken to dryness to afford thesubject butyl ester.

EXAMPLES 102-104

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure ofExample 101 with the appropriate alcohol affords the esters of thefollowing table.

                  TABLE V    ______________________________________    Example Alcohol      Product Ester    ______________________________________    102    isopropanol                     2-(6-carboisopropoxyhexyl)cyclopent-2-                     en-1-one    103    methanol  2-(6-carbomethoxyhexyl)cyclopent-2-en-                     1-one    104    ethanol   2-(6-carbethoxyhexyl)cyclopent-2-en-1-                     one    ______________________________________

EXAMPLE 105 Preparation of ethyl 9-oxoprostanoate

To a Grignard solution, prepared from 332 mg. of magnesium and 3.32 g.of n-octyl iodide in 10 ml. of diethyl ether under nitrogen atmosphere,is added 192 mg. of cuprous iodide-tris-n-butylphosphine complexfollowed by dropwise addition of 3 g. of2-(6-carbethoxyhexyl)cyclopent-2-en-1-one and the resulting mixture isstirred for 2 hours. Saturated ammonium chloride (50 m.) is addedfollowed by 25 ml. of water and 50 ml. of diethyl ether. The ether layeris washed successively with aqueous sodium thiosulfate solution,ammonium chloride solution, and water, dried with magnesium sulfate andtaken to dryness leaving an oil. Distillation of 0.06 mm. of mercury(bath to 190° ) gives 2 g. of material containing unreacted startingmaterial and 1.86 g. (42%) of residue which contains the desiredproduct. This material is chromatographed on Florisil®, an activatedmagnesium silicate. The product is eluted with 10% diethylether-in-hexane to give 737 mg. of an oil, which has no significantultraviolet absorption; λ_(max) ^(KBr) 5.75, 8.50 μ; nmr 2H quarter δ(OCH₂ of ester), 3H triplet 1.25 (CH₃ of ester), and 3H distortedtriplet 0.91 (terminal methyl); mass spectrum: m/e 352; vapor phasechromatography shows one peak.

EXAMPLE 106 Preparation of isopropyl 9-oxo-19,20-bisnorprostanoate

By replacing the n-octyl iodide and2-(6-carbethoxyhexyl)cyclopent-2-en-1-one employed in Example 105 withequimolecular quantities of n-hexyl bromide and2-(6-carboisopropoxyhexyl)cyclopent-2-en-1-one, respectively, andfollowing substantially the same procedure described in Example 105,there is obtained isopropyl 9-oxo-19,20-bisnorprostanoate.

EXAMPLE 107 Preparation of methyl 9-oxo-20-ethylprostanoate

The procedure of Example 105 is repeated, substituting equimolecularamounts of n-decyl chloride and2-(6-carbomethoxyhexyl)cyclopent-2-en-1-one, respectively, for then-octyl iodide and 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one employed inthat example. There is thus obtained methyl 9-oxo-20-ethylprostanoate.

EXAMPLE 108 Preparation of n-butyl9-oxo-14,15,16,17,18,19,20-heptanorprostanoate

The procedure of Example 105 is repeated, substituting equimolecularamounts of methyl iodide and2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one, respectively, for then-octyl iodide and 2-(6-carboethoxyhexyl)cyclopent-2-en-1-one employedin that example. There is thus obtained n-butyl9-oxo-14,15,16,17,18,19,20-heptanorprostanoate.

EXAMPLE 109 Preparation of n-butyl 9-oxo-18,19,20-trinorprostanoate

The procedure of Example 105 is repeated, substituting equimolecularamounts of n-amyl iodide and2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one, respectively, for then-octyl iodide and 2-(6-carboethoxyhexyl)cyclopent-2-en-1-one employedin that example. There is thus obtained n-butyl9-oxo-18,19,20-trinorprostanoate.

EXAMPLE 110 Preparation of ethyl 9-oxo-17,18,19,20-tetranorprostanoate

The procedure of Example 105 is repeated, substituting an equimolecularamount of n-butyl iodide for the n-octyl iodide employed in thatexample. There is thus obtained ethyl9-oxo-17,18,19,20-tetranorprostanoate.

EXAMPLE 111 Preparation of n-butyl 9-oxoprostanoate

The procedure of Example 105 is repeated, substituting an equimolecularamount of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one for the2-(6-carboethoxyhexyl)cyclopent-2-en-1-one employed in that example.There is thus obtained n-butyl 9-oxoprostanoate.

EXAMPLE 112 preparation of ethyl9-oxo-14,15,16,17,18,19,20-heptanorprostanoate

To a slurry of 38.09 g. (0.20 mole) of copper (I) iodide in 60 ml. ofdiethyl ether under nitrogen is added 238 ml. (0.39 mole) of 5.07%methyl lithium in ether maintaining a temperature -5° - -10° C. To theresulting solutin is added 23.83 g. (0.10 mole) of2-(6-carboethoxyhexyl)-2-cyclopentenone and the mixture is stirred at-10° C. for 1 hour. The mixture is hydrolyzed with saturated ammoniumchloride solution and the organic phase is separated, washed with waterand saturated brine, dried (Na₂ SO₄) and evaporaed to yield an oil.Distillation gives 23.4 g. of a colorless oil, b.p. 112°-115° C. (0.075mm.) which by nmr consists of 85% trans isomer and 15% cis isomer. IR -1745 cm⁻¹ (carbonyl) NMR: (CDCl₃) δ 0.90 doublet J=7.0 H₂ cis CH--CH₃ ;1.17 doublet J = 5.5 H₂ trans CH--CH₃.

EXAMPLE 113 Preparation of 9-oxoprostanoic acid

A suspension of 300 mg. of ethyl 9-oxoprostanoate in 20 ml. of aqueousmethanol (1:1) containing 300 mg. of potassium hydroxide is stirred at50° C. for 1 hour and then at room temperature for 18 hours. Theresulting solution is acidified with 1N hydrochloric acid, concentratedand extracted several times with diethyl ether. The combined etherextracts are washed with saturated sodium chloride solution, dried withanhydrous magnesium sulfate and taken to dryness to give 256 mg. (94%)of product as an oil;λ_(max) 5.75, 5.85 μ; nmr 1H broad singlet δ 9.89(carboxyl proton, exchangeable).

EXAMPLES 114-120

Saponification by the procedure of Example 113 of the alkyl estersindicated in the following table is productive of the prostanoic acidsof the table.

                  TABLE VI    ______________________________________           Starting Alkyl    Example           Prostanoate of                       Product Prostanoic Acid    ______________________________________    114    Example 106 9-Oxo-19,20-bisnorprostanoic acid    115    Example 107 9-Oxo-20-ethylprostanoic acid    116    Example 108 9-Oxo-14,15,16,17,18,19,20-heptanor-                       prostanoic acid    117    Example 109 9-Oxo-18,19,20-trinorprostanoic acid    118    Example 110 9-Oxo-17,18,19,20-tetranorprostanoic                       acid    119    Example 111 9-Oxoprostanoic acid    120    Example 112 9-Oxo-14,15,16,17,18,19,20-heptanor-                       prostanoic acid    ______________________________________

EXAMPLE 121 Preparation of the sodium salt of3-(n-heptyl)-2-(6-carboxyhexyl)cyclopentanone

In 25 ml. of methanol was dissolved 3.06 g. of3-(n-heptyl)-2-(6-carboxyhexyl)cyclopentanone and 0.54 g. of sodiummethoxide and the resulting solution was evaporated to dryness. Therewas thus obtained the sodium salt as a white powder.

EXAMPLE 122 Preparation of the potassium salt of3-(n-nonyl)-2-(6-carboxyhexyl)cyclopentanone

In 25 ml. of water was dissolved 3.34 g. of3-(n-nonyl)-2-(6-carboxyhexyl)cyclopentanone and 0.56 g. of pelletpotassium hydroxide and the resulting solution was evaporated todryness. There was thus obtained the potassium salt as an off whitepowder.

EXAMPLES 123-136

Treatment of the cyclopentenones of the following table with lithiodimethyl cuprate by the procedure described in Example 112 is productiveof the 9-oxo-14,15,16,17,18,19,20-heptanorprostanoate esters3-methyl-2-(ω-carbalkoxycyclopentanones! of the table.

                  TABLE VII    ______________________________________           Starting Alkyl           Cyclopentenone    Example           Ester of    Product 9-Oxo-prostanoate Ester    ______________________________________    123    Example 19  Ethyl 9-Oxo-6,7,14,15,16,17,18,                       19,20-Nonanorprostanoate    124    Example 27  Ethyl 9-Oxo-7a,7b-bishomo-14,15,                       16,17,18,19,20-heptanorprostanoate    125    Example 42  Ethyl 9-Oxo-2-ethyl-14,15,16,17,                       18,19,20-heptanorprostanoate    126    Example 52  Ethyl 9-Oxo-3,3-dimethyl-14,15,                       16,17,18,19,20-heptanorprostanoate    127    Example 57  Ethyl-9-Oxo-3-oxa-14,15,16,17,18,                       19,20-heptanorprostanoate    128    Example 61  Ethyl 9-Oxo-3-thia-14,15,16,17,18,                       19,20-heptanorprostanoate    129    Example 68  Ethyl 9-Oxo-7,14,15,16,17,18,19,                       20-octanorprostanoate    130    Example 18  Ethyl 9-Oxo-5,6,7,14,15,16,17,18,                       19,20-decanorprostanoate    131    Example 85  Ethyl 9-Oxo-2-fluoro-14,15,16,17,                       18,19,20-heptanorprostanoate    132    Example 89  Ethyl 9-Oxo-7a-homo-14,15,16,17,                       18,19,20-heptanorprostanoate    133    Example 94  Ethyl 9-Oxo-2-phenyl-14,15,16,17,                       18,19,20-heptanorprostanoate    134    Example 101 Butyl 9-Oxo-14,15,16,17,18,19,20-                       heptanorprostanoate    135    Example 102 Isopropyl 9-Oxo-14,15,16,17,18,                       19,20-heptanorprostanoate    136    Example 103 Methyl 9-Oxo-14,15,16,17,18,19,                       20-heptanorprostanoate    ______________________________________

EXAMPLE 137 Preparation of 9-oxo-15,16,17,18,19,20-hexanorprostanoate

A Grignard solution, prepared under nitrogen atmosphere at 45°-50° C.from 535 mg. of magnesium and 3.44 g. of ethyl iodide in 8 ml. oftoluene containing 1 mole of tetrahydrofuran per gram atom of magnesium,is added dropwise with stirring to a solution of 4.766 g. of2-(6-carbethoxyhexyl)2-cyclopentenone in 40 ml. of tetrahydrofurancontaining 330 mg. of cuprous iodide-tris-n-butylphosphine complex inthe cold. The resulting solution is stirred at room temperature for 1hour and then is poured into cold dilute hydrochloric acid and extractedwith ether. The combined extracts are washed with saline solution, driedover magnesium sulfate and evaporated to give 5.14 g. of an oil. Thecrude oil is dissolved in ether and treated with four equivalents ofaqueous potassium permanganate for 10 minutes. The mixture is filteredand the filtrate is washed with saline, dried over magnesium sulfate andevaporated. This residual material is further purified by silica gelchromatography to give 2.1 g. of a light yellow oil, IR 1740 cm⁻¹ (esterand carbonyls).

EXAMPLES 138-154

Treatment of the cyclopentenones of the following table by the proceduredescribed in Example 137 with the indicated Grignard reagent, preparedas required from ethyl iodide, propyl iodide, isopropyl iodie or butyliodide in the manner of Example 137, is productive of the alkyl9-oxoprostanoates of the table.

                  TABLE VIII    ______________________________________         Starting         Cyclopentenone                     Grignard   Product    Ex.  Ester of    Reagent   9-Oxoprostanoate Ester    ______________________________________    138   Example 103                     C.sub.2 H.sub.5 MgI                               Methyl 9-Oxo-15,16,17,18,                               19,20-hexanorprostanoate    139  Example 17  isopropyl-                               Ethyl 9-Oxo-13-methyl-15                     MgI       16,17,18,19,20-hexanor-                               prostanoate    140  Example 17  propyl-MgI                               Ethyl 9-Oxo-16,17,18,19,20-                               pentanorprostanoate    141  Example 19  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-6,7,15,16,17,                               18,19,20-octanorprostonoate    142  Example 19  propyl-MgI                               Ethyl 9-Oxo-6,7,16,17,18,                               19,20-heptanorprostanoate    143  Example 27  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-7a,7b-bishomo-                               15,16,17,18,19,20-hexanor-                               prostanoate    144  Example 42  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-2-ethyl-15,16,                               17,18,19,20-hexanorprost-                               anoate    145  Example 52  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-3,3-dimethyl-                               15,16,17,18,19,20-hexanor-                               prostanoate    146  Example 52  propyl-MgI                               Ethyl 9-Oxo-3,3-dimethyl-                               16,17,18,19,20-pentanor-                               prostanoate    147  Example 68  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-7,15,16,17,18,                               19,20-heptanorprostanoate    148  Example 68  propyl-MgI                               Ethyl 9-Oxo-7,16,17,18,19,                               20-hexanorprostanoate    149  Example 85  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-2-fluoro-15,16,                               17,18,19,20-hexanorprosta-                               noate    150  Example 85  propyl-MgI                               Ethyl 9-Oxo-2-fluoro-16,17,                               18,19,20-pentanorprostanoate    151  Example 89  C.sub.2 H.sub.5 MgI                               Ethyl 9-Oxo-7a-homo-15,16,                               17,18,19,20-hexanorprosta-                               noate    152  Example 19  butyl-MgI Ethyl 9-Oxo-6,7,17,18,19,                               20-hexanorprostanoate    153  Example 52  butyl-MgI Ethyl 9-Oxo-3,3-dimethyl-17,                               18,19,20-tetranorprostanoate    154  Example 85  butyl-MgI Ethyl 9-Oxo-2-fluoro-17,18,                               19,20-tetranorprostanoate    ______________________________________

EXAMPLE 155 Preparation of ethyl 9-oxo-18,19,20-trinorprostanoate

A mixture of 2 g. (6.49 mmoles) of ethyl9-oxo-18,19,20-trinor-13-prostenoate (Example 30) 1 g. of 10%palladium-in-charcoal in 50 ml. of ethanol is shaken in a Parr lowpressure hydrogenation apparatus at an initial hydrogen pressure of 30psi until hydrogen uptake ceased. The reaction mixture is filtered andconcentrated. The residue is dissolved in ether, washed with salinesolution, dried over magnesium sulfate and concentrated to give 1.94 g.of a light yellow oil, IR 1740 cm⁻¹ (ester and ketone carbonyls).

EXAMPLES 156-184

Saponification of the 9-oxoprostanoate esters of the following table bythe procedure of Example 113 is productive of the prostanoic acids ofthe table.

                  TABLE IX    ______________________________________           Starting           9-Oxoprostanoate           Ester of    Examples           Example No.  Product 9-Oxo-prostanoic Acid    ______________________________________    156    123          9-Oxo-6,7,14,15,16,17,18,19,20-                        nonanorprostanoic Acid    157    124          9-Oxo-7a,7b,bishomo-14,15,16,17,                        18,19,20-heptanorprostanoic Acid    158    125          9-Oxo-2-ethyl-14,15,16,17,18,19,                        20-heptanorprostanoic Acid    159    126          9-Oxo-3,3-dimethyl-14,15,16,17,18,                        19,20-heptanorprostanoic Acid    160    127          9-Oxo-3-oxa-14,15,16,17,18,19,20-                        heptanorprostanoic Acid    161    128          9-Oxo-3-thia-14,15,16,17,18,19,                        20-heptanorprostanoic Acid    162    129          9-Oxo-7,14,15,16,17,18,19,20-octa-                        norprostanoic Acid    163    130          9-Oxo-5,6,7,14,15,16,17,18,19,20-                        decanorprostanoic Acid    164    131          9-Oxo-2-fluoro-14,15,16,17,18,19,                        20-heptanorprostanoic Acid    165    132          9-Oxo-7a-homo-14,15,16,17,18,19,                        20-heptanorprostanoic Acid    166    133          9-Oxo-2-phenyl-14,15,16,17,18,19,                        20-heptanorprostanoic Acid    167    137          9-Oxo-15,16,17,18,19,20-hexanor-                        prostanoic Acid    168    139          9-Oxo-13-methyl-15,16,17,18,19,                        20-hexanorprostanoic Acid    169    140          9-Oxo-16,17,18,19,20-pentanor-                        prostanoic Acid    170    141          9-Oxo-6,7,15,16,17,18,19,20-octa-                        norprostanoic Acid    171    142          9-Oxo-6,7,16,17,18,19,20-heptanor-                        prostanoic Acid    172    143          9-Oxo-8a,7b-bishomo-15,16,17,18,                        19,20-hexanorprostanoate Acid    173    144          9-Oxo-2-ethyl-15,16,17,18,19,20-                        hexanorprostanoic Acid    174    145          9-Oxo-3,3-dimethyl-15,16,17,18,                        19,20-hexanorprostanoic Acid    175    146          9-Oxo-3,3-dimethyl-16,17,18,19,                        20-pentanorprostanoic Acid    176    147          9-Oxo-7,15,16,17,18,19,20-hepta-                        norprostanoic Acid    177    148          9-Oxo-7,16,17,18,19,20-hexanor-                        prostanoic Acid    178    149          9-Oxo-2-fluoro-15,16,17,18,19,                        20-hexanorprostanoic Acid    179    150          9-Oxo-2-fluoro-16,17,18,19,20-                        pentanorprostanoic Acid    180    151          9-Oxo-7a-homo-15,16,17,18,19,20-                        hexanorprostanoic Acid    181    152          9-Oxo-6,7,17,18,19,20-hexanor-                        prostanoic Acid    182    153          9-Oxo-3,3-dimethyl-17,18,19,20-                        tetraprostanoic Acid    183    154          9-Oxo-2-fluoro-17,18,19,20-tetra-                        noroprostanoic Acid    184    155          9-Oxo-18,19,20-trinorprostanoic                        Acid    ______________________________________

EXAMPLE 185 Preparation of Ethyl9-oxo-10a-homo-14,15,16,17,18,19,20-heptanorprostanoate

Treatment of ethyl 7-(cyclohex-2-en-1-one-2-yl)-heptanoate (Example 28)with lithio dimethyl cuprate in the manner of Example 112 is productiveof the subject compound.

EXAMPLE 186 Preparation of9-oxo-10a-homo-14,15,16,17,18,19,20-heptanorprostanoic Acid

Saponification of ethyl9-oxo-10a-homo-14,15,16,17,18,19,20-heptanorprostanoate (Example 185) bythe procedure of Example 113 is productive of the subject prostanoicacid.

EXAMPLE 187 Preparation of diethyl (5-chloro-1,1-dimethylpentyl)malonate

Magnesium (71 g. 2.92 moles) in 1 l. of ether containing a few crystalsof iodine is added dropwise to 1-chloro-4-bromobutane (500 g., 2.92moles) over a period of 30 minutes with stirring under nitrogen. Thereaction is maintained at a temperature of 0° C. to 5° C. by immersingin an acetone-Dry Ice bath periodically. After stirring for 30 minutesat room temperature, the solution is chilled to below 0° C. and is thentransferred to a dropping funnel from which it is added dropwise todiethyl isopropylidene malonate (440 g., 2.19 moles) A. C. Cope and E.M. Hancock, Jour. Amer. Soc., 60, 2644 (1938)! dissolved in 1000 ml. ofether containing the tri(n-butyl)phosphine complex of copper (I) iodide(57 g.) G. B. Kaufman and L. A. Teter, Inorganic Synthesis, 7, 9(1963)!at -10° C. with stirring under nitrogen over a period of two hours.After stirring at room temperature for 4 hours, the reaction mixture ispoured into cold dilute hydrochloric acid and is extracted with ether.The combined ether extracts are washed with saline solution, dried overmagnesium sulfate, and concentrated in vacuo to give 700 g. of crudeamber oil, which is distilled under vacuum to yield two fractions: 212.4g. with b.p. at 110° C-135° C. at 0.3 mm. and 100.0 g. with b.p. at 135°C.-145° C. at 0.3 mm. The total yield is 312.4 g. (49%).

EXAMPLE 188 Preparation of 3,3-dimethyl-7-chloroheptanoic acid

A mixture containing diethyl 5-(5-chloro-1,1-dimethylpentyl)malonate(648 g., 2.22 moles) potassium hydroxide (460 g.) and eight liters of1:1 isopropanol: water is stirred at room temperature overnight. Most ofthe isopropanol is distilled and the residue is diluted with water, andthen carefully acidified with conc. hydrochloric acid. The mixture isextracted with ether and the extracts are washed with water and saline,dried over magnesium sulfate and concentrated in vacuo to give 548 g. ofcrude oil. The oil is dissolved in three liters of diglyne which isheated under reflux for sixteen hours. About 2.7 l. of solvent isdistilled, and the remainder is diluted with water and extracted withether. The extracts are washed with saline, dried over magnesium sulfateand concentrated in vacuo to give 428 g. of crude oil (99%).

EXAMPLE 189 Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamideis added 500 ml. of thionyl chloride and the resulting solution istested under reflux for 3 hours. The reaction solution then isconcentrated in vacuo and the residual acid chloride is dissolved in aminimum amount of benzene and added slowly to a solution containing 1260ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine.After heating under reflux for one hour, the solution is concentratedand the residue is dissolved in ether washed with water, dilute sodiumbicarbonate solution and saline solution, dried over magnesium sulfateand concentrated to give 415 g. of crude oil, which is distilled undervacuum to yield two fractions: 46.6 g. boiling at 75° C. (0.3 mm.) and236.7 g. boiling at 75° C. - 80° C. (0.3 mm). The total yield is 283.3g. (60%) and the product is indicated to be 95% pure by g.l.c.

EXAMPLE 190 Preparation of methyl/ethyl2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentanone-2-carboxylate

Sodium hydride (67 g., 1.55 moles) is placed in a three l. round-bottomflask and to this is added 1.1 liters of glyme from a dropping funnelunder nitrogen flow and with stirring. To the resulting grayish mixtureis added the 2-carbalkoxycyclopentanone (mixed methyl and ethyl esters)dropwise over a period of 45 minutes with nitrogen flow whilst thetemperature is maintained in the range of 40°-55°. Ethyl3,3-dimethyl-7-chloroheptanoate (283 g., 1.28 moles) and potassiumiodide (195 g., 1.32 moles) are added and the mixture is heated atreflux overnight. After most of the solvent is distilled, the residue ismade acidic with dilute hydrochloric acid and is then extracted withether. The ether extracts are washed with water and saline solution,dried over magnesium sulfate, and concentrated in vacuo to 500 g. ofcrude yellow oil, which is distilled to give 405 g. (94% yield) of oilwith b.p. 140°-180° (0.8 mm).

EXAMPLE 191 Preparation of 7-(2-Cyclopentanone)-3,3 dimethylheptanoicacid

Methyl/Ethyl2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentanone-2-carboxylate (200 g.,0.6 moles), glacial acetic acid (180 ml) and 240 ml. of dilutedhydrochloric acid, prepared from 100 ml. of conc. hydrochloric acid and300 ml. of water, are placed in a 2 l. flask, containing a refluxcondenser and a magnetic stirrer. The mixture then is stirred at refluxfor 24 hours. The reaction mixture is cooled, 1 l. of water is added andthe mixture is extracted several times with benzene. The organicextracts are combined, washed with saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to an oil (173.5g.). The oil is rendered basic with sodium hydroxide solution, extractedwith benzene and made acidic with hydrochloric acid and reextracted withbenzene several times. The benzene layers are combined and washed withwater, saturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to yield 109.8 g. (78%) of crude oil, whichwas used without further purification in the next step.

EXAMPLE 192 Preparation of Ethyl7-(2-Cyclopentanone)-3,3-dimethylheptanoate

To a solution of 7-(2-cyclopentanone)-3,3-dimethylheptanoic acid (45 g.,0.22 mol.) in 285 ml. of chloroform containing three drops ofN,N-dimethylformamide is added dropwise 25 ml. of thionyl chloride. Thesolution is stirred at room temperature for 20 minutes, the solvent isremoved at reduced pressure and the residual acid chloride is dissolvedin a minimum amount of benzene and added slowly to a solution containing115 ml. of ethanol, 230 ml. benzene and 30 ml. of collodine. Thissolution is heated under reflux for 15 minutes and then concentrated.The residue is dissolved in ether, washed with water, diluted sodiumbicarbonate solution and saline solution, dried over magnesium sulfateand concentrated to give 51 g. of crude oil. Distillation gives 40 g.(67%) b.p. 135°-145° (0.1 mm.) of oil.

EXAMPLE 193 Preparation of1-Acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene

A solution of ethyl 7-(2-cyclopentanone)-3,3-dimethylheptanoate (90 g.,0.336 mol.) and p-toluenesulfonic acid (0.94 g.) in 250 ml. of aceticanhydride is heated to boiling under partial reflux, allowing distillateat 118° or less (i.e. acetic acid) to escape then a vigreux columnequipped with a condenser to collect the distillate. After 10 hours 130ml. of distillate is collected. Another 50 ml. of acetic anhydride isadded and the reaction is heated for 5 more hours; an additional 125 ml.of acetic anhydride is added, the reaction is heated for 7 more hours;finally another 50 ml. of acetic anhydride is added and heating iscontinued for 4 more hours. The solution is cooled and poured(cautiously) into a cold (0°-5°) mixture of saturated aqueous sodiumbicarbonate (400 ml.) and hexane (250 ml.). The resulting cold mixtureis stirred for 30 minutes during which time portions of solid sodiumbicarbonate are added periodically until carbon dioxide evalutionceases. The hexane layer is separated and washed with saturated sodiumchloride solution until the washings are neutral, dried over magnesiumsulfate and treated with Darco decolorizing charcoal for clarificationand then evaporated to dryness leaving an amber colored oil (87.5 g.,84%).

EXAMPLE 194 Preparation of2-(6-Carboxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g.,0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate(11.8 g.) cooled in an ice-bath is added dropwise over a period ofthirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride(31 ml.). After stirring in the cold for an additional 45 minutes theorange colored chloroform layer is separated and washed with dilutesodium bisulfite and saturated saline solution, dried over magnesiumsulfate and taken to dryness in vacuo (bath temperature: 35°-40°)leaving an amber colored oil. A slurry of 100 ml. ofN,N-dimethylacetamide and 16.5 g. of CaCO₃ is stirred and heated toreflux under nitrogen flow. The above dried oil is added from a droppingfunnel rapidly, maintaining reflux and nitrogen flow for thirty minutes.The cooled reaction mixture is filtered, and the precipitate is washedwith ether. The filtrate is poured into two liters ice-cold water and isextracted with ether. The combined extracts and washing is washed withwater, saturated saline, treated with decolorizing charcoal, filtered.The solvent evaporated in vacuo to give 24 g. (77%) of subject product.

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR16## wherein R₁ is hydrogen or alkyl having up to fourcarbon atoms; R₂ is a straight chain alkyl group having from one to tencarbon atoms, inclusive; and Z is a divalent radical of the formulae:##STR17## wherein n is an integer from three to five, inclusive; thestereoisomers thereof; and the cationic salts thereof when R₁ ishydrogen.
 2. A compound according to claim 1 wherein R₁ is ethyl, R₂ ismethyl, and Z is --(CH₂)₄ --O--CH₂ --.
 3. A compound according to claim1 wherein R₁ is ethyl, R₂ is methyl, and Z is --(CH₂)₄ --S--CH₂ --.
 4. Acompound according to claim 1 wherein R₁ is ethyl, R₂ is methyl, and Zis ##STR18##
 5. A compound according to claim 1 wherein R₁ is hydrogen,R₂ is methyl, and Z is --(CH₂)₄ --O--CH₂ --.
 6. A compound according toclaim 1 wherein R₁ is hydrogen, R₂ is methyl, and Z is --(CH₂)₄ --S--CH₂--.
 7. A compound according to claim 1 wherein R₁ is hydrogen, R₂ ismethyl, and Z is ##STR19##
 8. A compound according to claim 1 wherein R₁is hydrogen, R₂ is n-octyl, and Z is --(CH₂)₄ --S--CH₂ --.
 9. A compoundaccording to claim 1 wherein R₁ is methyl, R₂ is n-octyl, and Z is--(CH₂)₄ --S--CH₂ --.
 10. A compound according to claim 1 wherein R₁ isethyl, R₂ is n-octyl, and Z is --(CH₂)₄ --S--CH₂ --.